Gambogic acid(GA), a caged xanthone derivative isolated from Garcinia Hanburyi, exhibits significant antitumor activity and has advanced to phase Ⅱ clinical trials for lung cancer treatment in China. However, the clinical application of GA is severely hindered by its inherent limitations, including poor water solubility, a lack of targeting specificity, and significant side effects. Novel drug delivery systems not only overcome these pharmacological deficiencies but also integrate multiple therapeutic modalities, transcending the limitations of monotherapeutic approaches. In this study, we designed a multifunctional nanodelivery platform(PDA-PEG-Fe(Ⅲ)-GOx-GA) using polydopamine(PDA) as the core material. After the modification of PDA with polyethylene glycol(PEG), Fe(Ⅲ) ions, glucose oxidase(GOx), and GA were sequentially loaded via coordination interactions, electrostatic adsorption, and hydrophobic interactions, respectively. This system demonstrated excellent physiological stability, hemocompatibility, and photothermal conversion efficiency. Notably, under dual stimuli of pH and near-infrared(NIR) irradiation, PDA-PEG-Fe(Ⅲ)-GOx-GA achieved controlled GA release, with a cumulative release rate of 58.3% at 12 h, 3.6-fold higher than that under non-stimulated conditions. Under NIR irradiation, the synergistic effects of PDA-mediated photothermal therapy, Fe(Ⅲ)-induced chemodynamic therapy, GOx-generated starvation therapy, and GA-mediated chemotherapy resulted in effective inhibition of tumor cell proliferation(91.5% inhibition rate) and induction of apoptosis(83.3% apoptosis rate). This multi-modal approach realized a comprehensive treatment strategy for lung cancer, integrating various therapeutic pathways.
Xanthones/pharmacology* ; Humans ; Polymers/chemistry* ; Glucose Oxidase/pharmacology* ; Indoles/chemistry* ; Drug Delivery Systems ; Drug Carriers/chemistry* ; Nanoparticles/chemistry* ; Cell Line, Tumor

Diabetic retinopathy is a common blinding complication in diabetic patients. Compared with conventional fundus color photography, fundus fluorescein angiography can dynamically display retinal vessel permeability changes, offering unique advantages in detecting early small lesions such as microaneurysms. However, existing intelligent diagnostic research on diabetic retinopathy images primarily focuses on fundus color photography, with relatively insufficient research on complex lesion recognition in fluorescein angiography images. This study proposed an adaptive multi-label classification model (D-LAM) to improve the recognition accuracy of small lesions by constructing a category-adaptive mapping module, a label-specific decoding module, and an innovative loss function. Experimental results on a self-built dataset demonstrated that the model achieved a mean average precision of 96.27%, a category F1-score of 91.21%, and an overall F1-score of 94.58%, with particularly outstanding performance in recognizing small lesions such as microaneurysms (AP = 1.00), significantly outperforming existing methods. The research provides reliable technical support for clinical diagnosis of diabetic retinopathy based on fluorescein angiography.
Diabetic Retinopathy/diagnostic imaging* ; Humans ; Fluorescein Angiography ; Microaneurysm/diagnostic imaging* ; Retinal Vessels ; Algorithms

Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to pyruvate kinase M2 (PKM2)-dependent conventional caspase-3/gasdermin E (GSDME) cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-programmed death-1 (anti-PD-1). In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.
Pyroptosis/immunology* ; Humans ; Endoplasmic Reticulum/immunology* ; Animals ; Nogo Proteins/antagonists & inhibitors* ; Mice ; Cell Line, Tumor ; Xanthones/pharmacology* ; Neoplasms/pathology* ; Mice, Nude

Ten novel xanthones, garpedunxanthones A-G (1-5, 6a/6b, 7a/7b) and nujiangxanthone Q (8), along with sixteen known analogs (9-24), were isolated from Garcinia pedunculata and G. nujiangensis. Their structures were elucidated through high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) data, comprehensive nuclear magnetic resonance (NMR) spectroscopic analyses, and electronic circular dichroism (ECD) calculations. All compounds without cytotoxicity were assessed for anti-inflammatory properties by measuring the inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 cells. Structure-activity relationships are also discussed. Compounds 7b, 19, and 21 exhibited significant anti-inflammatory activity with IC₅₀ values of 16.44 ± 0.69, 14.28 ± 0.78, and 10.67 ± 3.28 μmol·L^-1, respectively. Enzyme-linked immunosorbent assay (ELISA) demonstrated that compounds 7b, 19, and 21 inhibited the expression of pro-inflammatory cytokines TNF-α and IL-6 in a dose-dependent manner. The inhibitory effect of compound 21 on IL-6 at 20 μmol·L^-1 was comparable to that of the positive control. In network pharmacology studies, potential targets of compounds and inflammation were identified from PharmMapper and GeneCards databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the overlapped targets were intricately associated with major pathogenic processes linked to inflammation, including positive regulation of mitogen-activated protein kinase (MAPK) cascade, protein kinase activity, NO synthase regulator activity, MAPK signaling pathway, and EGFR tyrosine kinase inhibitor resistance.
Xanthones/therapeutic use* ; Garcinia ; Anti-Inflammatory Agents/therapeutic use* ; Plant Preparations/therapeutic use* ; Structure-Activity Relationship ; Nitric Oxide/metabolism* ; RAW 264.7 Cells ; Animals ; Mice ; Enzyme-Linked Immunosorbent Assay ; Mitogen-Activated Protein Kinase Kinases/metabolism* ; Circular Dichroism

Gambogic acid, a caged xanthone compound derived from Garcinia, has been proven to be an important substance basis for the pharmacological effects of the plant. In recent years, it has received continuous attention due to its broad and significant pharmacological activities. Modern pharmacological investigations have demonstrated that gambogic acid endows various therapeutic effects such as anti-inflammatory, antioxidant, and anti-tumor activities, as well as benefits in retinopathy, organ protection, anti-microbial infection, bone protection, and neuropathic pain relief. Nevertheless, there is currently a lack of systematic summary and integration of the pharmacological effects and mechanisms of gambogic acid, which is critical for advancing the clinical application of this natural product. In addition, current research has raised concerns about potential safety risks associated with gambogic acid, such as organ toxicity, developmental toxicity, and hemolysis. Given this, this paper systematically reviewed and summarized the pharmacological effects, mechanisms, and toxicological profiles of gambogic acid, aiming to provide reference and data support for its clinical translation.
Xanthones/toxicity* ; Humans ; Animals ; Drugs, Chinese Herbal/toxicity* ; Garcinia/chemistry*

OBJECTIVES: To compare the clinical efficacy and safety of acupuncture and sodium hyaluronate eye drop in the treatment of aqueous deficiency dry eye. METHODS: A total of 60 patients (120 eyes) with aqueous deficiency dry eye were randomly divided into an observation group (30 cases, 1 case dropped out) and a control group (30 cases, 1 case dropped out). In the control group, sodium hyaluronate eye drop were used, one drop at a time, 4 times a day, for 14 consecutive days. In the observation group, acupuncture was applied at bilateral Shangjingming (Extra), Cuanzhu (BL 2), Sizhukong (TE 23), Taiyang (EX-HN 5), and Tongziliao (GB 1) , once a day, treatment for 6 days with the interval of 1 day was required, for 14 consecutive days. The tear meniscus height (TMH), Schirmer Ⅰ test (SⅠT), ocular surface disease index (OSDI) score, non-invasive tear break-up time (NIBUT), and corneal fluorescein sodium staining (FLS) score were compared between the two groups before and after treatment, and the safety of the treatment of the two groups was observed. RESULTS: Compared with those before treatment, after treatment, TMH, SⅠT and NIBUT were increased (<i>Pi><0.01, <i>Pi><0.05), and FLS scores were decreased (<i>Pi><0.01) in the two groups; the score of OSDI was reduced (<i>Pi><0.01) in the observation group. After treatment, in the observation group, TMH and SⅠT were higher than those in the control group (<i>Pi><0.01), and the score of OSDI was lower than that in the control group (<i>Pi><0.01). No adverse reactions and adverse events were observed in the two groups. CONCLUSIONS Acupuncture and sodium hyaluronate eye drop can both effectively treat aqueous deficiency dry eye, acupuncture has obvious advantages in improving TMH and basic tear secretion, and reducing the subjective symptoms of patients. Acupuncture for dry eye is safe.
Humans ; Hyaluronic Acid ; Acupuncture Therapy ; Dry Eye Syndromes/therapy* ; Eye ; Tears ; Ophthalmic Solutions ; Fluorescein

OBJECTIVE: To evaluate the effect of intense pulsed light (IPL) in the treatment of chronic hordeolum. METHODS: Patients with chronic hordeolum who underwent IPL treatment were enrolled in this study. According to the severity of hordeolum, the patients were treated with IPL 3 to 5 times. Patients' satisfaction and visual analog scale scores for ocular discomfort symptoms before and after treatment were collected. The number, congestion, long diameter, short diameter and area of nodules were also recorded and measured. Finally, eyelid margin signs, meibum quality, meibomian gland expressibility, meibomian gland dropout, tear meniscus height, and corneal fluorescein staining were scored. RESULTS: 20 patients were enrolled in this study. The eyelid margins were congestive and swollen, with blunt rounding or irregularity. The meibum was cloudy or toothpaste-like. The meibomian gland expressibility, meibomian gland dropout and tear meniscus height were reduced. The cornea showed scattered fluorescein staining. After treatment, score of visual analog scale, congestion and size of nodules were significantly reduced. Eyelid margin signs, meibum quality, meibomian gland expressibility, tear meniscus height and corneal fluorescein staining scores were improved. Meibomian gland dropout had no significant change. No side effects occurred during treatment. CONCLUSIONS IPL is beneficial for the treatment of chronic hordeolum.
Humans ; Hordeolum ; Meibomian Glands ; Tears ; Fluoresceins

The chemical constituents from the stems and leaves of Cratoxylum cochinchinense were isolated and purified using silica gel, ODS gel, and Sephadex LH-20 gel column chromatography, as well as preparative HPLC. The chemical structures of all isolated compounds were identified on the basis of their physicochemical properties, spectroscopic analyses, and the comparison of their physicochemical and spectroscopic data with the reported data in literature. As a result, 21 compounds were isolated from the 90% ethanol extract of the stems and leaves of C. cochinchinense, which were identified as cratocochine(1), 1-hydroxy-3,7-dimethoxyxanthone(2), 1-hydroxy-5,6,7-trimethoxyxanthone(3), ferrxanthone(4), 3,6-dihydroxy-1,5-dimethoxyxanthone(5), 3,6-dihydroxy-1,7-dimethoxyxanthone(6), 1,2,5-trihydroxy-6,8-dimethoxyxanthone(7), securixanthone G(8), gentisein(9), 3,7-dihydroxy-1-methoxyxanthone(10), pancixanthone B(11), garcimangosxanthone A(12), pruniflorone L(13), 9-hydroxy alabaxanthone(14), cochinchinone A(15), luteolin(16), 3,5'-dimethoxy-4',7-epoxy-8,3'-neolignane-5,9,9'-triol(17), N-benzyl-9-oxo-10E,12E-octadecadienamide(18), 15-hydroxy-7,13E-labdadiene(19), stigmasta-4,22-dien-3-one(20), and stigmast-5-en-3β-ol(21). Among these isolates, compound 1 was a new xanthone, compounds 2-5, 7, 8, 12, and 16-21 were isolated from the Cratoxylum plant for the first time, and compounds 11 and 13 were obtained from C. cochinchinense for the first time. Furthermore, all isolated compounds 1-21 were appraised for their anti-rheumatoid arthritis activities by MTS method through measuring their anti-proliferative effect on synoviocytes in vitro. As a result, xanthones 1-15 displayed notable anti-rheumatoid arthritis activities, which showed inhibitory effects on the proliferation of MH7A synoviocytes with the IC_(50) values ranging from(8.98±0.12) to(228.68±0.32) μmol·L~(-1).
Synoviocytes ; Clusiaceae/chemistry* ; Xanthones/analysis* ; Plant Leaves/chemistry* ; Cell Proliferation ; Arthritis

Eight compounds were isolated from ethyl acetate fraction of 80% ethanol extract of the hulls of Garcinia mangostana by silica gel, Sephadex LH-20 column chromatography, as well as prep-HPLC methods. By HR-ESI-MS, MS, 1D and 2D NMR spectral analyses, the structures of the eight compounds were identified as 16-en mangostenone E(1), α-mangostin(2), 1,7-dihydroxy-2-(3-methy-lbut-2-enyl)-3-methoxyxanthone(3), cratoxyxanthone(4), 2,6-dimethoxy-para-benzoquinone(5), methyl orselinate(6), ficusol(7), and 4-(4-carboxy-2-methoxyphenoxy)-3,5-dimethoxybenzoic acid(8). Compound 1 was a new xanthone, and compound 4 was a xanthone dimer, compound 5 was a naphthoquinone. All compounds were isolated from this plant for the first time except compounds 2 and 3. Cytotoxic bioassay suggested that compounds 1, 2 and 4 possessed moderate cytotoxicity, suppressing HeLa cell line with IC_(50) va-lues of 24.3, 35.5 and 17.1 μmol·L~(-1), respectively. Compound 4 also could suppress K562 cells with an IC_(50) value of 39.8 μmol·L~(-1).
Humans ; Garcinia mangostana/chemistry* ; HeLa Cells ; Antineoplastic Agents ; Magnetic Resonance Spectroscopy ; Xanthones/pharmacology* ; Garcinia/chemistry* ; Plant Extracts/chemistry* ; Molecular Structure

OBJECTIVE: To analyze the effects of mangiferin combined with bortezomib on the proliferation, invasion, apoptosis and autophagy of human Burkitt lymphoma Raji cells, as well as the expression of CXC chemokine receptors (CXCRs) family, and explore the molecular mechanism between them to provide scientific basis for basic research and clinical work of Burkitt lymphoma. METHODS: Raji cells were intervened with different concentrations of mangiferin and bortezomib alone or in combination, then cell proliferation was detected by CCK-8 assay, cell invasion ability was detected by Transwell chamber method, cell apoptosis was detected by Annexin V/PI double-staining flow cytometry, apoptosis, autophagy and Akt/mTOR pathway protein expression were detected by Western blot, and the expression changes of CXCR family was detected by real-time quantitative PCR (RT-qPCR). RESULTS: Different concentrations of mangiferin intervened Raji cells for different time could inhibit cell viability in a concentration- and time-dependent manner (<i>ri> =-0.682, <i>ri> =-0.836). When Raji cells were intervened by combination of mangiferin and bortezomib, compared with single drug group, the proliferation and invasion abilities were significantly decreased, while the apoptosis level was significantly increased (<i>Pi> <0.01). Mangiferin combined with bortezomib could significantly up-regulate the expression of pro-apoptotic protein Bax and down-regulate the expression of anti-apoptotic protein Bcl-2 after intervention in Raji cells. Caspase-3 was also hydrolyzed and activated, and then induced the apoptosis of Raji cells. Mangiferin combined with bortezomib could up-regulate the expression of LC3Ⅱ protein in Raji cells, and the ratio of LC3Ⅱ/LC3Ⅰ in cells was significantly up-regulated compared with single drug or control group (<i>Pi> <0.01). Mangiferin combined with bortezomib could significantly inhibit the phosphorylation levels of Akt and mTOR, inhibit the proliferation and invasion of Raji cells by inhibiting Akt/mTOR pathway, and induce cell autophagy and apoptosis. Mangiferin and bortezomib could down-regulate the expressions of <i>CXCR4i> and <i>CXCR7i> mRNA after single-agent intervention in Raji cells, and the down-regulations of <i>CXCR4i> and <i>CXCR7i> mRNA expression were more significant when the two drugs were combined (<i>Pi> <0.01). Mangiferin alone or combined with bortezomib had no significant effect on <i>CXCR5i> mRNA expression in Raji cells (<i>Pi> >0.05), while the combination of the two drugs could down-regulate the expression of <i>CXCR3i> (<i>Pi> <0.05). CONCLUSION Mangiferin combined with bortezomib can synergistically inhibit the proliferation and invasion of Raji cells, and induce autophagy and apoptosis. The mechanism may be related to the inhibition of Akt/mTOR signaling pathway, down-regulation of anti-apoptotic protein Bcl-2 and up-regulation of pro-apoptotic protein Bax, and the inhibition of the expression of CXCR family.
Humans ; Antineoplastic Agents/therapeutic use* ; Apoptosis/drug effects* ; Apoptosis Regulatory Proteins/immunology* ; Autophagy/immunology* ; bcl-2-Associated X Protein/immunology* ; Bortezomib/therapeutic use* ; Burkitt Lymphoma/immunology* ; Cell Line, Tumor ; Cell Proliferation/drug effects* ; Drug Therapy, Combination ; Proto-Oncogene Proteins c-akt ; Proto-Oncogene Proteins c-bcl-2 ; Receptors, CXCR/immunology* ; RNA, Messenger ; TOR Serine-Threonine Kinases ; Xanthones/therapeutic use*