Xiaoxv Dong

Objectives: This study aimed to develop curcumin nanoparticles (Cur@PCL-PEG-MF/cRGDfc) with retinal-targeting capability and to evaluate their biological effects and pharmacological mechanisms in vitro. Methods: After synthesis of the carrier framework, metformin (MF) and cRGDfc were conjugated to the carrier material using the carbodiimide method and Michael addition reaction, respectively. Subsequently, self-assembled nanoparticles were formed from the carrier and curcumin under specific conditions. The materials were characterized by spectroscopy, chromatography, elemental analysis, energy-dispersive spectroscopy and X-ray diffraction. The efficacy of the formulation was evaluated in two cell lines, ARPE-19 and HUVEC-T1. In addition, the pharmacological mechanism was explored using transcriptome sequencing as a complementary approach. Key Findings: Self-assembled nanoparticles were successfully prepared by combining the two modified carrier materials, PCL-PEG-MF and PCL-PEG-cRGDfc, with curcumin. The nanoparticles exhibited an encapsulation efficiency of 78.09%, a particle size of 162.33 nm, and a zeta potential of −23.28 mV and displayed a spherical morphology. They showed sustained release in simulated physiological conditions and stronger affinity for ARPE-19 cells under oxidative stress. Nearly 100% of the nanoparticles were internalized by the cells, which was accompanied by reduced ROS and LDH release and decreased DNA fragmentation. In addition, the nanoparticles inhibited neovascularization by reducing VEGF-A release, thereby potentially protecting the retina in macular degeneration and reducing choroidal hemorrhage. Further analyses showed that curcumin and its nanoformulations significantly reduced the expression of inflammatory factors such as IL-1β and IL-18, lowered the protein levels of Caspase-1, GSDMD-N, and NLRP3, and increased AMPK levels. Conclusions: Using PCL-PEG as the carrier framework, MF and cRGDfc were conjugated to construct a curcumin-loaded nanoparticle with retinal-targeting capability. This nanoparticle, characterized by a small particle size, sustained release, and targeted delivery to retinal pigment epithelium (RPE) cells under oxidative stress, alleviated oxidative stress-induced damage. Its therapeutic effect may be mediated, at least in part, by interference with the AMPK/mTOR pathway and activation of the NLRP3/Caspase-1/GSDMD pathway.

The incidence of primary liver cancer is increasing annually, with extremely high mortality and suboptimal therapeutic outcomes. The inefficient presentation of tumor antigens and low infiltration of specific cytotoxic T lymphocytes (CTLs) result in insufficient immunogenicity, which limits the efficacy of immunotherapy. Despite the popularity of immune checkpoint inhibitors (ICIs), insufficient immune activation means only a small subset of hepatocellular carcinoma (HCC) patients exhibit clinical responses to ICIs, showing significant inter-individual variability. The activation of the cyclic GMP-AMP synthase(cGAS)- stimulator of interferon genes(STING) pathway initiates the expression of type I interferons (IFNs) and inflammatory cytokines, promoting the formation of a pro-inflammatory environment at the tumor site. This pathway enhances anti-tumor immune responses by facilitating antigen processing and presentation, T cell priming and activation, and remodeling of the immunosuppressive microenvironment. Our research found that cucurbitacin B (CuB), a natural component derived from traditional Chinese medicine, had significant anti-hepatocellular carcinoma properties and exerted anti-tumor effects through the cGAS-STING pathway. Specifically, CuB regulated ferroptosis by down-regulating the expression of Solute Carrier Family 7 Member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) and upregulating the expression of Transferrin Receptor Protein 1 (TFR1) and Long-chain Acyl-CoA Synthetase 4 (ACSL4). These actions involved lipid substrates, iron ion homeostasis, and antioxidant defense systems. The release of mitochondrial DNA (mtDNA) triggered by ferroptosis activated the cGAS-STING immune signaling pathway, leading to the up-regulation of cGAS, phosphorylated STING (p-STING), phosphorylated TANK-binding kinase 1 (TBK1), phosphorylated Interferon regulatory factor3 (IRF3), and Interferon-β (IFN-β). This cascade activation pattern provides new insights into the drug treatment of tumors.

Pyroptosis is a type of programmed cell death (PCD) with pro-inflammatory properties, which is characterized by the swelling with bubbles and the release of LDH and inflammatory cell cytokines. Polyphyllin II (PPII) is the main active ingredient of the Chinese herb Rhizoma Paridis and has been proven to exert high efficacy against a variety of malignant tumors. At present, the anti-tumor research on PPII mainly focuses on apoptosis that is an anti-inflammatory type of PCD, but other potential modes of death cell death and mechanisms of PPII remain to be discovered. Here, we first found that PPII could effectively inhibit the growth of hepatocellular carcinoma (HCC) cells via pyroptosis. After treatment with PPII, the morphology of swelling with bubbles and the formation of pores in the cell membrane in HCC cells were observed, and LDH and cell cytokines (IL-1β, IL-18, IL-6, TNF-α, IFN-β, and IFN-γ) were released. Furthermore, the flow cytometry results showed that PPII could activate oxidative stress by increasing Ca²⁺ influx, thereby promoting the production of ROS to exert anti-tumor effects. RNA sequencing revealed that pyroptosis is closely linked to several signaling pathways, including the MAPK, TNF, Rap1, mTOR, and FoxO pathways, as well as the PD-L1 expression and PD-1 checkpoint pathway. An in vivo study demonstrated that PPII treatment suppressed liver tumor growth in mice by pyroptosis in a dose-dependent manner, and it showed no obvious side effects within a certain range. The Western blot results of tumor tissues revealed that the pyroptosis effect of PPII on liver cancer was associated with the activation of the NLRP3/Caspase1/GSDMD pathway, which upregulates the expression of NLRP3, Cleaved-Caspase 1, GSDMD-N, IL-1β, and IL-18 proteins and downregulates the expression of pro-Caspase 1 and GSDMD proteins. In summary, our findings revealed the pyroptosis effect and mechanism of PPII in HCC cells in vitro and in vivo, suggesting that PPII may be used as a potential pyroptosis inducer for HCC treatment in the future.

Diabetic nephropathy (DN) represents a severe microvascular complication of diabetes mellitus. As a Traditional Chinese Medicine (TCM) with extensive clinical applications, Ligustri Lucidi Fructus (LLF) exhibits significant anti-DN activity. However, the underlying pharmacological mechanisms, crucial components, and targets for LLF in DN treatment remain unclear. By integrating network pharmacology, molecular docking, and molecular dynamics simulations, the bioactive compounds, potential therapeutic targets, and underlying mechanisms of LLF in the treatment of DN were elucidated, followed by biological validation in a palmitic acid (PA)-induced MPC5 podocyte injury model. Among the 383 DN-related LLF targets identified, TNF emerged as a pivotal one, demonstrating potential binding interaction with the active components salidroside (Sal), apigenin (Api), and tormentic acid (TA). Moreover, Gene Expression Omnibus (GEO) database and KEGG enrichment analysis collectively highlighted the cytosolic DNA-sensing pathway. Notably, the cGAS-STING pathway is central to this pathway. Experimental studies further demonstrated that LLF-containing serum exerted a protective effect on MPC5 podocytes through cGAS-STING pathway suppression. Overall, these findings elucidate the pleiotropic mechanisms underlying LLF’s protective effects against DN, integrating compound–target–pathway interactions and thus offering a rationale for further investigation.

Psoriasis, a chronic inflammatory skin disorder, is driven by dysregulated immune responses and keratinocyte dysfunction. Here, we explore the therapeutic potential of Astilbin (AST), a flavonoid with potent anti-inflammatory properties, in modulating ferroptosis and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in IL-17-stimulated HaCaT keratinocytes. Our psoriatic cell model recapitulated key pathological features, including hyperproliferation, membrane integrity loss, mitochondrial dysfunction, and heightened oxidative stress, alongside elevated proinflammatory cytokine levels. Ferroptosis-related biomarkers were significantly altered, with increased malondialdehyde (MDA) accumulation, reduced glutathione (GSH) levels, iron overload (Fe²⁺), and enhanced lipid peroxidation (detected via C11-BODIPY). Mechanistically, mitochondrial damage triggered cytoplasmic leakage of mitochondrial DNA (mtDNA), activating the cGAS-STING pathway, as evidenced by upregulated pathway-associated protein expression. AST intervention effectively mitigated these pathological changes by suppressing ferroptosis and modulating cGAS-STING signaling. These findings reveal a dual-pathway regulatory mechanism, positioning AST as a promising therapeutic candidate for psoriasis. By elucidating the interplay between ferroptosis and the cGAS-STING pathway, this study provides new insights into psoriatic inflammation and offers a rationale for targeting these pathways in therapeutic strategies.

Hypoxic damage to retinal pigment epithelial (RPE) cells and subsequent neovascularization are key factors in the pathogenesis of branch retinal vein occlusion (BRVO). Naringin (NG), a naturally occurring flavanone glycoside, has demonstrated significant antioxidant and anti-neovascular activities. However, the regulatory effects and mechanisms of NG on ferroptosis in BRVO are yet to be explored. Our study aimed to investigate the protective effects of NG on RPE cells under hypoxic stress and to elucidate the underlying molecular mechanisms. Our findings revealed that NG significantly reduced cytotoxicity induced by cobaltous chloride (CoCl₂) and also inhibited vascular proliferation in the retina, thereby attenuating choroidal neovascularization. NG pretreatment largely countered the overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA) triggered by hypoxic damage, while also restoring levels of the antioxidants glutathione (GSH) and superoxide dismutase (SOD). Furthermore, NG pretreatment significantly activated the expression of hypoxia-inducible factor-1 alpha (HIF-1α) and its downstream heme oxygenase-1 (HO-1) and NADPH dehydrogenase (NQO1). In conclusion, NG not only inhibits neovascularization but also alleviates inflammation in RPE cells by modulating the HO-1/GPX4 pathway to inhibit ferroptosis. These findings highlight the potential of NG as a promising therapeutic agent for the treatment of BRVO.

Curcumin (CUR) has a bright future in the treatment of cancer as a natural active ingredient with great potential. However, curcumin has a low solubility, which limits its clinical application. In this study, IRMOF-10 was created by the direct addition of triethylamine, CUR was loaded into IRMOF-10 using the solvent adsorption method, and the two were characterized using a scanning electron microscope (SEM), X-ray diffraction (XRD), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TG) methods, and Brunauer–Emmett–Teller (BET) analysis. We also used the MTT method, 4′,6-diamidino-2-phenylindole (DAPI) staining, the annexin V/PI method, cellular uptake, reactive oxygen species (ROS), and the mitochondrial membrane potential (MMP) to perform a safety analysis and anticancer activity study of IRMOF-10 and CUR@IRMOF-10 on HepG2 cells. Our results showed that CUR@IRMOF-10 had a CUR load of 63.96%, with an obvious slow-release phenomenon. The CUR levels released under different conditions at 60 h were 33.58% (pH 7.4) and 31.86% (pH 5.5). Cell experiments proved that IRMOF-10 was biologically safe and could promote curcumin entering the nucleus, causing a series of reactions, such as an increase in reactive oxygen species and a decrease in the mitochondrial membrane potential, thereby leading to cell apoptosis. In summary, IRMOF-10 is an excellent drug carrier and CUR@IRMOF-10 is an effective anti-liver cancer sustained-release preparation.

The incidence of ocular surface disease (OSD) is increasing, with a trend towards younger ages. However, it is difficult for drugs to reach the deep layers of the cornea due to ocular surface barriers, and bioavailability is less than 5%. In this study, DSPE-PEG2000 was modified with L-valine (L-Val), and an HS15/DSPE-PEG2000-L-Val nanomicelle delivery system containing baicalin (BC) (BC@HS15/DSPE-PEG2000-L-Val) was constructed using thin-film hydration, with a high encapsulation rate, small particle size and no irritation to the ocular surface. Retention experiments on the ocular surface of rabbits and an in vivo corneal permeation test showed that, compared with the control, nanomicelles not only prolonged retention time but also enhanced the ability to deliver drugs to the deep layers of the cornea. The results of a protein inhibition and protein expression assay showed that nanomicelles could increase uptake in human corneal epithelial cells (HCEC) through energy-dependent endocytosis mediated by clathrin, caveolin and the carrier pathway mediated by PepT1 by inhibiting the overexpression of claudin-1 and ZO-1 and suppressing the expression of PepT1-induced by drug stimulation. These results indicate that BC@HS15/DSPE-PEG2000-L-Val is suitable for drug delivery to the deep layers of the ocular surface, providing a potential approach for the development of ocular drug delivery systems.