Aurantio-obtusin, an anthraquinone compound, isolated from dried seeds of Cassia obtusifolia L. (syn. Senna obtusifolia; Fabaceae) and Cassia tora L. (syn. Senna tora). Although the biological activities of Semen Cassiae have been reported, the anti-inflammatory mechanism of aurantio-obtusin, its main compound, on RAW264.7 cells, remained unknown. We investigated the anti-inflammatory effect of aurantio-obtusin on lipopolysaccharide- (LPS)-induced RAW264.7 cells in vitro and elucidated the possible underlying molecular mechanisms. Nitric oxide production (NO) and prostaglandin E₂ (PGE₂) were measured by the Griess colorimetric method and enzyme-linked immunosorbent assay (ELISA), respectively. Protein expression levels of cyclooxygenase 2 (COX-2) were monitored by cell-based ELISA. Interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) synthesis were analyzed using ELISA. The mRNA expression of nitric oxide synthase (iNOS), COX-2, and the critical pro-inflammatory cytokines (IL-6 and TNF-α) were detected by quantitative real-time PCR. Aurantio-obtusin significantly decreased the production of NO, PGE₂, and inhibited the protein expression of COX-2, TNF-α and IL-6, which were similar to those gene expression of iNOS, COX-2, TNF-α and IL-6 (p < 0.01). Consistent with the pro-inflammatory gene expression, the Aurantio-obtusin efficiently reduced the LPS-induced activation of nuclear factor-κB in RAW264.7 cells. These results suggested that aurantio-obtusin may function as a therapeutic agent and can be considered in the further development of treatments for a variety of inflammatory diseases. Further studies may provide scientific evidence for the use of aurantio-obstusin as a new therapeutic agent for inflammation-related diseases.

Oxidative stress is the main pathogenesis of diabetic microangiopathy, which can cause microvascular endothelial cell damage and destroy vascular barrier. In this study, it is found that carnosol protects human microvascular endothelial cells (HMVEC) through antioxidative mechanisms. First, we measured the antioxidant activity of carnosol. We showed that carnosol pretreatment suppressed tert-butyl hydroperoxide (t-BHP)-induced cell viability, affected the production of lactate dehydrogenase (LDH) as well as reactive oxygen species (ROS), and increased the produce of nitric oxide (NO). Additionally, carnosol promotes the protein expression of vascular endothelial cadherin (VE-cadherin) to keep the integrity of intercellular junctions, which indicated that it protected microvascular barrier in oxidative stress. Meanwhile, we investigated that carnosol can interrupt Nrf2-Keap1 protein−protein interaction and stimulated antioxidant-responsive element (ARE)-driven luciferase activity in vitro. Mechanistically, we showed that carnosol promotes the expression of heme oxygenase 1(HO-1) and nuclear factor-erythroid 2 related factor 2(Nrf2). It can also promote the expression of endothelial nitric oxide synthase (eNOS). Collectively, our data support the notion that carnosol is a protective agent in HMVECs and has the potential for therapeutic use in the treatments of microvascular endothelial cell injury.

Cancer is the second most common cause of death globally. The anticancer effects of Tanshinone II_A (Tan II_A) has been confirmed by numerous researches. However, the underlying mechanism remained to be integrated in systematic format. Systems biology embraced the complexity of cancer; therefore, a system study approach was proposed in the present study to explore the anticancer mechanism of Tan II_A based on network pharmacology. Agilent Literature Search (ALS), a text-mining tool, was used to pull protein targets of Tan II_A. Then, pharmacological clustering was applied to classify obtained hits, the anticancer module was analysed further. The top ten essential nodes in the anticancer module were obtained by ClusterONE. Functional units in the anticancer module were catalogued and validated by Gene Ontology (GO) analysis. Meanwhile, KEGG and Cell Signalling Technology Pathway were employed to provide pathway data for potential anticancer pathways construction. Finally, the pathways were plotted using Cytoscape 3.5.1. Furthermore, in vitro experiments with five carcinoma cell lines were conducted. A total of 258 proteins regulated by Tan II_A were identified through ALS and were visualized by protein network. Pharmacological clustering further sorted 68 proteins that intimately involved in cancer pathogenesis based on Gene Ontology. Subsequently, pathways on anticancer effect of Tan II_A were delineated. Five functional units were clarified according to literature: including regulation on apoptosis, proliferation, sustained angiogenesis, autophagic cell death, and cell cycle. The GO analysis confirmed the classification was statistically significant. The inhibiting influence of Tan II_A on p70 S6K/mTOR pathway was revealed for the first time. The in vitro experiments displayed the selectivity of Tan II_A on HeLa, MDA-MB-231, HepG2, A549, and ACHN cell lines, the IC₅₀ values were 0.54 μM, 4.63 μM, 1.42 μM, 17.30 μM and 204.00 μM, respectively. This result further reinforced the anticancer effect of Tan II_A treatment. The current study provides a systematic methodology for discovering the coordination of the anticancer pathways regulated by Tan II_A via protein network. And it also offers a valuable guidance for systematic study on the therapeutic values of other herbs and their active compounds.

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Immune checkpoint blockade (ICB) generates sustained responses in immunogenic cancers, but its effectiveness is limited in tumors lacking immune activity. Here, we construct a bioinspired bimetallic ions functionalized nanoscale metal-organic framework (NMOF) single-atom nanozyme (SAzyme) loaded with doxorubicin (Dox) (NMOF-Fe/Cu-Dox nanocomposite) to effectively trigger anti-tumor immune responses while addressing the immunosuppressive tumor microenvironment (TME). The NMOF-Fe/Cu-Dox nanocomposite has been demonstrated to efficiently reverse the TME by generating reactive oxygen species and oxidizing glutathione. Camouflaging NMOF-Fe/Cu-Dox nanocomposites with bioinspired cancer cell membrane (NMOF-Fe/Cu-Dox@M) enables its navigation to the tumor region through homologous targeting. The highly efficient uptaken by cancer cells selectively induced synergistic ferroptosis and cuproptosis in these cells. Furthermore, in vitro and in vivo experiments demonstrate that the ferroptosis in cancer cells can polarize tumor-associated macrophages (TAMs) towards anti-tumoral M1 phenotype and significantly diminish pro-tumoral M2 phenotype. We find that NMOF-Fe/Cu-Dox@M could induce the ferroptosis of M2 macrophages, while no effect to M1 macrophages. In addition, a significant increase of anti-tumor infiltrating CD8 ⁺ T cells, while a remarkable decrease of CD4 ⁺ regulatory T cells were observed. These findings suggested that NMOF-Fe/Cu-Dox@M could efficiently modulate TME, enhance tumoricidal immunity and elevate the therapeutic efficiency of ICB. Moreover, the combination of NMOF-Fe/Cu-Dox@M with αPD-1 effectively eradicated hepatocellular carcinoma cells in vivo , outperforming the use of either NMOF-Fe/Cu-Dox@M or αPD-1 alone. In summary, our study presents a therapeutic strategy that leverages coordinated ferroptosis and cuproptosis with therapeutic efficiency of ICB, underscoring the promise of combined chemoimmunotherapy.