查找使用阿拉丁产品的科研文献

Oridonin loaded amphiphilic hyaluronic acid polymeric micelle with tunable redox sensitive property for CD44 targeted lung cancer therapy

Xuan Shaoyan,Yang Shenglei,Mao Yuqin,Chen Zhiyong,Zhu Yue,Zhou Ying,Huang Jie,Zhu Xiuliang,Wang Zuhua

Lung cancer remains one of the most prevalent and lethal malignancies worldwide. Oridonin (ORI) exhibits remarkable anti-lung cancer activity. Nevertheless, its clinical application in lung cancer therapy is severely hindered by poor solubility, fast metabolism, insufficient tumor penetration, and low selectivity. In this study, we developed a redox-responsive polymeric micelle (HA-cys-TOS) targeting the CD44 receptor to improve ORI bioavailability and tumor targeting. The polymer was synthesized via esterification and verified by 1 H NMR. Our data showed that ORI@HA-cys-TOS exhibited good stability, biosafety and redox-responsive sustained release. Compared to HepG2 cells, ORI@HA-cys-TOS exhibited significantly enhanced internalization ability in A549 cells, likely due to HA binding to the CD44 receptor overexpressed on A549 cells. Unexpectedly, the enhanced targeted accumulation of ORI@HA-cys-TOS micelles in vivo was also observed in both subcutaneous and in situ lung cancer tissues. In vivo and in vitro antitumor studies demonstrated that ORI@HA-cys-TOS micelles exhibited significantly greater antitumor activity compared to free ORI. Notably, no side-effects were observed during the 21 days experimental period. This study provides an experimental basis for advancing ORI toward clinical personalized lung cancer therapy by targeting CD44 and responding to the tumor redox microenvironment.

A H2S-releasing oridonin derivative improves diabetic wound healing based on antibacterial activity and regulation of macrophage phagocytosis

Yuzhen Jia,Lang Lin,Xinyi Shi,Erbei Ge,Dahong Li,Fanxing Xu,Chun Chu

H 2 S-releasing oridonin derivative promotes wound healing in diabetic mice. • H 2 S-releasing oridonin derivative inhibits S. aureus and MRSA growth and biofilm formation. • H 2 S-releasing oridonin derivative upregulates TLR2 expression and autophagy-mediated phagocytosis of S. aureus . Chronic diabetic wounds are characterized by persistent bacterial burden and impaired healing. Oridonin, a natural diterpenoid, shows potential for wound repair but is limited by poor solubility and bioavailability. A promising strategy to enhance oridonin's efficacy involves its conjugation with H 2 S donors. In our study, a type 1 diabetic mouse wound model was treated topically with hydrogels containing oridonin, α-thioctic acid, or H 2 S-releasing oridonin derivative D5 for 14 days. D5 treatment induced epithelial thickening, collagen deposition, and upregulation of Ki67 and CD31, as evidenced by histological and immunofluorescence analyses. Blood agar assays confirmed D5 reduced wound bacterial colonization. In vitro, D5 inhibited the growth and biofilm formation of Staphylococcus aureus and methicillin-resistant S. aureus , and disrupted preformed biofilms. Moreover, D5 dose-dependently enhanced RAW264.7 phagocytosis of S. aureus . Mechanistically, it upregulated TLR2 and MyD88 protein expression and activated PI3K/AKT/mTOR-mediated autophagy, while the effects were abolished by TLR2 siRNA transfection, the TLR2 inhibitor C29, and the autophagy inhibitor 3-MA. Molecular docking, molecular dynamics, and thermal shift assays supported a potential interaction between D5 and TLR2. In addition, D5 treatment was associated with increased TLR2 protein stability, potentially involving proteasome-related regulation. Collectively, these findings suggest that D5 promotes diabetic wound healing by reducing bacterial burden and enhancing TLR2-dependent autophagy-mediated phagocytosis, providing a promising therapeutic strategy for diabetic wound repair. Download: Download high-res image (88KB) Download: Download full-size image

Oridonin combined with cisplatin synergistically induces apoptosis by activating the NOXA-BCL2 axis in esophageal squamous cell carcinoma

Qihang Guo,Yue Mao,Jiyu Zhang,Yangyang Zhou,Yue Zhao,Ying Li,Jinglong Lv,Huiyu Yang,Bingrong Liu

Esophageal cancer, a malignant neoplasm originating from the epithelial cells of the esophagus, predominantly manifests as esophageal squamous cell carcinoma (ESCC) in approximately 90% of cases in China. Cisplatin-based chemotherapy regimens remain the first-line therapeutic option for ESCC, however, the five-year overall survival rate of patients is disappointingly low. Oridonin, a bioactive diterpenoid extracted from the traditional Chinese medicine herb Donglingcao, has demonstrated inhibitory effects against various malignancies. Currently, research on the combination of oridonin and cisplatin for the treatment of ESCC is limited. This study aims to elucidate the potential synergistic anti-cancer effects of oridonin in combination with cisplatin on ESCC, along with the underlying synergistic molecular mechanisms. In vitro experiments revealed that the combination of oridonin and cisplatin could synergistically inhibit ESCC cell proliferation, migration, invasion. The synergistic effect also induced cell cycle arrest and promoted apoptosis via the mitochondrial pathway by augmenting NOXA transcriptional activity and activating the NOXA-BCL2 axis. In vivo experiments corroborated these findings, showing a marked reduction in the growth of subcutaneous xenograft tumors in mice treated with the combination, without exacerbating the cisplatin-associated side effects such as weight loss or hepatic and renal toxicity. In conclusion, the combination of oridonin and cisplatin can synergistically inhibit the development of ESCC through the activation of the NOXA-BCL2 axis signaling pathway. This treatment is both safe and effective,   presenting a promising prospect for combined therapeutic application in ESCC management.

Wnt/β-catenin signaling pathway is involved in induction of apoptosis by oridonin in colon cancer COLO205 cells

Heqi Bu,Dianlei Liu,Junhui Cui,Ke Cai,Feng Shen

Background Oridonin has been demonstrated to have anticancer effect on all kinds of cancer cells and it has shown anti-tumor activity in some tumors partially via the inactivation of Wnt/β-catenin signaling pathway. The study investigated the anticancer effect of oridonin on colon carcinoma cell line COLO205 and explored underlying mechanism. Methods Cell Counting Kit-8 (CCK-8) assay was performed to assess cell viability. Flow cytometry was performed to analyze the apoptosis. The key target genes and proteins involved in Wnt/β-catenin pathway were detected by quantitative polymerase chain reaction (qPCR) and Western blotting. The xenograft tumor model of colon cancer COLO205 cell was introduced to detect anti-tumor effects in vivo . Transferase-mediated dUTP nick end labeling (TUNEL) assay was adopted to test the apoptotic cells in the tumor tissues. Results Oridonin inhibited the proliferation of colon cancer COLO205 cells in a dose-dependent and time-dependent manner. Oridonin induced apoptosis by increasing the cleavage of caspases in vitro . Furthermore, the expression levels of β-catenin and its downstream targets, including c-myc, cyclinD1 and survivin were significantly reduced. Nevertheless the knockdown of β-catenin by specific small interfering RNA (siRNA) could augment the anti-proliferative and pro-apoptotic effects by oridonin in COLO205 cells. Meanwhile, oridonin also increased protein expression level of glycogen synthase kinase 3β (GSK3β) and decreased the phosphorylation level of GSK3β. In vivo , oridonin treatment significantly suppressed tumor growth of COLO205 cell xenografts, and which was accompanied by the restrain of Wnt/β-catenin pathway. Conclusions Our present study demonstrated that the growth inhibition and apoptosis induction in colon cancer COLO205 cells by oridonin could be partially mediated through discontinuing Wnt/β-catenin signaling pathway.

Oridonin Promotes Apoptosis in Rheumatoid Arthritis Fibroblast-like Synoviocytes Through PERK/eIF2α/CHOP of Endoplasmic Reticulum Stress Pathway

Shoudi He,Changsheng Huang,Ning Tan,Jianyong Zhang

Oridonin (ORI), derived from Chinese herbs Rabdosia rubescens, has anti-inflammatory, proapoptotic, anticancer effects. Previous studies have found that ORI induces apoptosis in rheumatoid arthritis fibroblast synovial cells (RA-FLSs), but this mechanism is not clear. We will investigate the apoptosis mechanism of ORI on RA-FLSs. RA-FLSs were treated with various concentrations of ORI (0, 5, 10, 15, 20, 25, and 30 μM) for 24 h. CCK8, LDH, and hochest/PI assay determined the viability, cytotoxicity, and death of ORI on RA-FLSs. The endoplasmic reticulum probe was used to observe structural changes of endoplasmic reticulum in RA-FLSs. RNA expression was detected with RNA sequencing analysis and quantitative real-time PCR. The PERK/eIF2α/CHOP pathway protein of the endoplasmic reticulum was verified with Western Blot. Our results show that ORI induced the apoptosis of RA-FLSs from CCK8, LDH, and Hochest/PI. The endoplasmic reticulum distribution was altered in RA-FLSs after being treated with ORI. Bioinformatics analysis of RNA sequencing data found that 1453 genes were elevated. The PERK/eIF2α/CHOP pathway of the endoplasmic reticulum was regulated from the Gene ontology and KEGG analysis. The results of quantitative real-time PCR and Western blot analysis verified the regulation of PERK/eIF2α/CHOP pathway in RA-FLSs. Our data imply that the endoplasmic reticulum's PERK/eIF2α/CHOP signaling pathway is certainly implicated in the induction of RA-FLS apoptosis by ORI. This study has important implications for the pharmacological effects of ORI and the treatment of RA.

Suppression of PERK/eIF2α/CHOP pathway enhances oridonin-induced apoptosis by inhibiting autophagy in Small-Cell lung cancer cells

Linhao Xu,Yuxin Jiang,Yanli Bi,Senwen Zheng,Yirong Wu,Yihao Wu,Yizhou Xu,Jian Chen

Chinese herbs have been used to treat small-cell lung cancer (SCLC) due to their low toxicity and significant efficacy. This study focused on oridonin, a natural compound extracted from Rabdosia rubescens, and aimed to investigate its potential antitumor activity on SCLC and to evaluate the synergistic effect of combining oridonin with other small molecules. In this study, oridonin exhibited a dual effect. At lower concentrations, it suppressed the cell viability of SCLC cells (H1688 and H446). At high concentrations, oridonin induced SCLC cell apoptosis, damaged HBE cells in vitro and compromised the function of the liver and heart in vivo . The lower concentration of oridonin induced autophagy by enhancing the expression of p62 and the LC3B-II/LC3B-I ratio. This phenomenon might be associated with the activation of the protein kinase RNA-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α)/growth arrest and DNA damage-inducible gene 153 (CHOP/GAD153) pathway. Therefore, the combined effect of oridonin with GSK2606414 or 3- methyladenine increased apoptosis in SCLC cells and reduced tumor growth. A similar phenomenon was observed after oridonin was combined with p62 or CHOP RNA interference treatment. Simultaneously, the combination of oridonin and GSK2606414 exhibited therapeutic efficacy without manifesting adverse effects. Our findings suggest that oridonin at lower concentrations can induce autophagy by activating the PERK/eIF2α/CHOP signaling pathway. The inhibition of the PERK/eIF2α/CHOP pathway could enhance oridonin therapeutic responses by triggering apoptosis. The novel therapeutic approach of combining oridonin with a PERK inhibitor is promising as a strategy for the treatment of SCLC.

Oridonin impedes breast cancer growth by blocking cells in S phase and inhibiting the PI3K/AKT/mTOR signaling pathway.

Weijie Zhang,Lei Shi,Wei Zhou,Xin Liu,Yuan Xi,Xinyin Wang,Ya Li,Xia Xu,Youcai Tang

Breast cancer is one of the most common cancers. Oridonin, a traditional Chinese medicine, is believed to inhibit tumor growth, but its particular effects on breast cancer remain unknown. In this study, we examined oridonin's effects on 4T1, MCF-7, and MDAMB-231 cellular activity using CCK8. Scratch assays were used to detect oridonin's effects on cellular migration. Oridonin's effects on the breast cancer cell cycle were studied using flow cytometry, and expression of cell cycle related proteins p53, CDK2, and p21 was detected using Western blot assays. Metabolomics assays were used to detect changes in small molecule metabolites and metabolic pathways in breast cancer cells after treatment with oridonin. Oridonin's effects on breast cancer growth were also studied using xenograft mice. Metabolomics assays were used to detect changes in metabolites and metabolic pathways in xenograft mouse plasma in a control group, model group, and drug administration group. Experimental results showed that oridonin could significantly inhibit breast cancer growth both in vivo and in vitro. Scratch experiments showed that oridonin could inhibit breast cancer cell migration. Oridonin was also able to arrest cells in S phase by affecting several cell cycle-related proteins, including p53, CDK2, and p21. Metabolomic analysis of 4T1 cells identified a total of 33 differential metabolites, including multiple amino acids (such as l-Glutamic acid, l-Asparagine, l-Histidine, l-Valine, and l-Isoleucine). KEGG pathway enrichment analysis showed significant changes in aminoacyl-tRNA biosynthesis, and in multiple amino acid metabolic pathways. Plasma metabolomic analyses of xenograft mice revealed 28 differentially-expressed metabolites between the different animal model groups, including multiple amino acids. KEGG pathway analysis showed significant alterations in multiple amino acid metabolic pathways in oridonin-treated mice. Additionally, changes in the expression of PI3K, AKT and mTOR proteins, as well as in branched amino acids, suggest that oridonin affects the PI3K/AKT/mTOR signaling pathway by inhibiting the biosynthesis of valine, leucine and isoleucine. Taken together, our results suggest that oridonin has strong anti-tumor activity in vitro and in vivo, and has potential as an adjuvant to breast cancer treatment regimens.

Enhanced lysosomal escape of cell penetrating peptide-functionalized metal–organic frameworks for co-delivery of survivin siRNA and oridonin

Mengru Cai,Yu Yao,Dongge Yin,Rongyue Zhu,Tingting Fu,Jiahui Kong,Kaixin Wang,Jing Liu,Aina Yao,Yidan Ruan,Wenjuan Shi,Qian Zhu,Jian Ni,Xingbin Yin

In recent years, small interfering RNA (siRNA) has been widely used in the treatment of human diseases, especially tumors, and has shown great appeal. However, the clinical application of siRNA faces several challenges. Insufficient efficacy, poor bioavailability, poor stability, and lack of responsiveness to a single therapy are the main problems affecting tumor therapy. Here, we designed a cell-penetrating peptide (CPP)-modified metal organic framework nanoplatform (named [email protected] @survivin [email protected] , [email protected] ) for targeted co-delivery of oridonin (ORI), a natural anti-tumor active ingredient) and survivin siRNA in vivo. This can improve the stability and bioavailability of siRNA and the efficacy of siRNA monotherapy. The high drug-loading capacity and pH-sensitive properties of zeolite imidazolides endowed the [email protected] with lysosomal escape abilities. The Polyethylene glycol (PEG)-conjugated CPP (PEG-CPP33) coating significantly improved the uptake in the [email protected] in vitro and in vivo. The results showed that the co-delivery of ORI and survivin siRNA greatly enhanced the anti-tumor effect of [email protected] , demonstrating the synergistic effect between ORI and survivin siRNA. In summary, the novel targeted nanobiological platform loaded with ORI and survivin siRNA presented herein showed great advantages in cancer therapy, and provides an attractive strategy for the synergistic application of chemotherapy and gene therapy.

Design, synthesis, and biological evaluation of oridonin derivatives as novel NLRP3 inflammasome inhibitors for the treatment of acute lung injury

Mengting Li,Lingyu Ma,Jiahao Lv,Zhe Zheng,Wenyu Lu,Xunkai Yin,Weijiang Lin,Ping Wang,Jian Cui,Lihong Hu,Jian Liu

Acute lung injury (ALI) is a severe respiratory disorder closely associated with the excessive activation of the NLRP3 inflammasome. Oridonin ( Ori ), a natural diterpenoid compound, had been confirmed as a specific covalent NLRP3 inflammasome inhibitor, which was completely different from that of MCC950 . However, the further clinical application of Ori was limited by its weak inhibitory activity against NLRP3 inflammasome (IC 50 = 1240.67 nM). Fortunately, through systematic structure-optimization of Ori , D6 demonstrated the enhancement of IL-1β inhibitory activity (IC 50 = 41.79 nM), which was better than the parent compound Ori . Then, by using SPR, molecular docking and MD simulation, D6 was verified to directly interact with NLRP3 via covalent and non-covalent interaction. The further anti-inflammatory mechanism studies were revealed that D6 could inhibit the activation of NLRP3 inflammasome without affecting the initiation phase of NLRP3 inflammasome activation, and D6 was a broad-spectrum and selective NLRP3 inflammasome inhibitor. Finally, D6 demonstrated a favorable therapeutic effect on LPS-induced ALI in mice model, and the potent pharmacodynamic effect of D6 was correlated with the specific inhibition of NLRP3 inflammasome activation in vivo . Thus, D6 is proved as a potent NLRP3 inhibitor, and has the potential to develop as a novel anti-ALI agent.

A novel conjunction of folate-targeted carbon nanotubes containing protohemin and oridonin-liposome loaded microbubbles for cancer chemo-sonodynamic therapy

Chuan-Jin Wang,Heng-Zhi Wang,Wei Li

Oridonin exerts dual therapeutic effects in MASLD mice by integrating lipid homeostasis and drug bioactivation via the LXRα–CES1/CES2 pathway

Jiang Huan-guo,Zhan Zhi-kun,Tian Ling-min,Chen Yu-lian,Cai Mei-qun,Ge Guang-bo,Chen Xin,Wei Chuan-liang,Tang Lan

Carboxylesterases CES1 and CES2 are the pivotal hepatic enzymes involved in triglyceride (TG) hydrolysis and prodrug metabolism, yet their expression and activity are suppressed in metabolic dysfunction-associated steatotic liver disease (MASLD). Liver X receptor alpha (LXRα) is known to play a crucial role in maintaining the constitutive expression of CES1 in human liver cells. Oridonin (ORI) is a diterpene derived from a traditional Chinese herb that possesses antitumor, anti-inflammatory, and antimicrobial activities. We previously demonstrated that ORI, as a natural LXRα agonist, activated the LXRα-ATGL/EPT1 pathway, correcting the TG/phosphatidylethanolamine (PE) lipid imbalance induced by obesity and thereby improving MASLD. Here, we investigated the regulatory role of LXRα on CES1/CES2 expression in MASLD liver and elucidated the underlying molecular mechanisms of ORI’s lipid-lowering effects. A high-fat diet (HFD)-induced steatosis model was established in mice. The mice were treated with ORI (100 mg·kg − 1 ·d − 1 , i.g.) from the 16th to the 24th week. RNA-seq analysis in MASLD patients demonstrated that LXRα is a key transcriptional regulator of CES1 and CES2. LXRα knockout (LXRα − / − ) mice exhibited aggravated HFD-induced steatosis and impaired metabolic conversion of the CES1/CES2 substrates, oseltamivir and irinotecan. This deficiency resulted in a corresponding increase in their drug exposure (AUC) by 154.5% and 26.2%, respectively. Mechanistically, LXRα directly bound to liver X receptor response elements (LXREs) in the promoter regions of CES1 (−183/−165 bp) and CES2 (−1870/−1852 bp) to drive transcription in HepG2 cells. Furthermore, ORI (2.5, 5, 10 μM) dose-dependently restored CES1/CES2 expression and activity, reducing lipid accumulation. Silencing of CES1 or CES2 abolished ORI’s lipid-lowering effect, confirming their essential roles. These findings establish the LXRα-CES1/CES2 pathway as a pivotal node integrating hepatic lipid homeostasis and drug metabolism, positioning ORI as a promising therapeutic agent for MASLD.

Microneedles incorporating oridonin micelles and Cu(II)-polydopamine provide effective inflammatory regulation and antibacterial effects for the healing of infected diabetic wounds

Wenbin Nan,Hao Wang,Linxiao Li,Jiulong Du,Xiangjuan Wei,Dongmei Wang,Yan Yang,Yongxue Wang,Dan Ding,Hongli Chen

The persistence of non-healing diabetic wounds is frequently attributed to excessive inflammation and bacterial infections. Therefore, strategies that target the reduction of inflammation while simultaneously inhibiting bacterial proliferation may offer an effective approach to overcoming this clinical challenge. In this study, we have developed an innovative formulation of hyaluronic acid (HA)-based dissolving microneedles (Cu(II)-PDA/ORI MNs) that incorporate oridonin (ORI) and Cu(II)-PDA nanoparticles, specifically designed for the treatment of chronic wounds in diabetic murine models. Our findings demonstrate that the composite MNs exhibit robust mechanical properties, facilitate drug delivery to the deeper layers of the skin, and exhibit favorable cytocompatibility and hemocompatibility. The encapsulation of ORI within the MNs effectively modulates the phenotype of RAW264.7 macrophages and exhibits significant anti-inflammatory properties, thereby contributing to the reduction of excessive inflammation within the wound microenvironment. Cu(II)-PDA nanoparticles significantly mitigate the toxicity associated with Cu(II) while retaining substantial antibacterial efficacy. Furthermore, they effectively promote wound angiogenesis, thereby expediting the wound healing process. Consequently, these Cu(II)-PDA/ORI MNs emerge as promising candidates for multifunctional wound dressing applications.