查找使用阿拉丁产品的科研文献

Oridonin Protects against Myocardial Ischemia–Reperfusion Injury by Inhibiting GSDMD-Mediated Pyroptosis

Jiahui Lin,Xianhui Lai,Xiaoxi Fan,Bozhi Ye,Lingfeng Zhong,Yucong Zhang,Ruiyin Shao,Si Shi,Weijian Huang,Lan Su,Miaomiao Ying

Pyroptosis serves a crucial function in various types of ischemia and reperfusion injuries. Oridonin, a tetracycline diterpene derived fromRabdosia rubescens, can significantly inhibit the aggregation of NLRP3-mediated inflammasome. This experiment is aimed at investigating the effect of oridonin on pyroptosis in mice cardiomyocytes. Based on the models of myocardial ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/R), Evans Blue/TTC double staining, TUNEL staining, and Western blotting were applied to determine the effects of oridonin on myocardial damage, cellular activity and signaling pathways involved in pyroptosis. During I/R and H/R treatments, the extent of gasdermin D-N domains was upregulated in cardiomyocytes. Apart from that, oridonin improved cell survival in vitro and decreased the myocardial infarct size in vivo by also downregulating the activation of pyroptosis. Finally, the expression levels of ASC, NLRP3 and p-p65 were markedly upregulated in cardiomyocytes after H/R treatment, whereas oridonin suppressed the expression of these proteins. The present experiment revealed that myocardial I/R injury and pyroptosis can be alleviated and inhibited by oridonin pretreatment via NF-κB/NLRP3 signaling pathway, both in vivo and in vitro. Therefore, oridonin may serve as a potentially novel agent for the clinical treatment of myocardial ischemia-reperfusion injuries.Keywords:oridonin;cardiac ischemia/reperfusion injury;pyroptosis;GSDMD

Static and dynamic studies of adsorption by four macroporous resins to enrich oridonin from Rabdosia rubescens

Ling Meng,Xia Gui,Zhi Yun

Oridonin, one of the active ingredients in Rabdosia rubescens ( R. rubescens ), has been reported to induce cell apoptosis and cell cycle arrest in many cancers. Conventional extraction methods tend to result in unsatisfied enrichment and poor quality of oridonin present in a given biomass. This paper aims to evaluate the performance and separation characteristics of four different macroporous resins to arrive at the most suitable methodology for the isolation and purification of high-quality oridonin. Static absorption kinetics, thermodynamic and dynamic adsorption were evaluated. HP-20 was selected for further study due to its high adsorption capacity of 32 mg·g −1 and desorption ratio with 98.5%. The pseudo-second-order model was considered to be the most suitable for kinetic results, and Langmuir model was chosen to better describe the absorption thermodynamics. Under optimum conditions (flow rate of 4 ml·min −1 , bed depth with 6 cm and initial concentration of 2.15 mg·ml −1 ), the effective content of oridonin increased from 33.9% to 79.1% in the dry extract with a recovery of 81% and the purity of oridonin improved from 76% to 93%. The results confirm that HP-20 provides an efficient method to purify most oridonin from R. rubescens .

Hepatoprotective effects of oridonin against bisphenol A induced liver injury in rats via inhibiting the activity of xanthione oxidase

Xinying Wang,Ming Gao,Zihan Wang,Weiqi Cui,Jingxian Zhang,Weijie Zhang,Yu Xia,Bo Wei,Youcai Tang,Xia Xu

Bisphenol A (BPA) is widely used to manufacture packaging materials for various daily necessities and causes harmful effects in organs, especially liver injury, by generating oxidative stress. Oridonin, an active diterpenoid isolated from Rabdosia rubescens (Hemsl.) Hara , has been reported to possess a wide range of pharmacological activities including anti-inflammatory, antioxidative and antiapoptotic effects. However, the role of oridonin in BPA--induced liver injury and its potential protective mechanism have not been well characterized. In this research, we explored the metabolic alterations in the liver tissue of rats after exposure to BPA with or without pretreatment with oridonin for 14 days by metabolomics analysis based on UPLC-MS/MS. Rats were randomly divided into groups as follows: Control, Vehicle, Oridonin (10 mg/kg), Bisphenol A (500 mg/kg), bisphenol A + Oridonin (500 + 10 mg/kg), Bisphenol A + Diammonium glycyrrhizinate (500 + 40 mg/kg). The biochemical results showed that oridonin significantly reduced the levels of AST and ALT ( P  < 0.05), ameliorated the abnormal histopathological changes and reduced hepatic apoptosis compared with the BPA group. Furthermore, metabolomics results revealed that purine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism were reprogrammed, based on 28 identified significant differential metabolites among the Vehicle, BPA and BPA + oridonin groups. In-depth studies demonstrated that pretreatment with oridonin may play a protective role by restoring BPA-induced changes in oxidative stress and the activity of oxidase (XOD) ( P  < 0.05). Additionally, oridonin could inhibit the activity of XOD by binding to it, therefore decreasing the reactive oxygen species (ROS) level, upregulating the content of hypoxanthine and xanthine, and reducing the level of uric acid in the liver ( P  < 0.05). This research presents the potential protective mechanisms of oridonin on BPA-induced liver injury at the metabolic level, which might be used to identify new protective agents that prevent BPA-induced liver injury.

Nanostructured lipid carriers used for oral delivery of oridonin: An effect of ligand modification on absorption

Xiaotong Zhou,Xingwang Zhang,Yanghuan Ye,Tianpeng Zhang,Huan Wang,Zhiguo Ma,Baojian Wu

Oridonin (Ori) is a natural compound with notable anti-inflammation and anti-cancer activities. However, therapeutic use of this compound is limited by its poor solubility and low bioavailability. Here a novel biotin-modified nanostructured lipid carrier (NLC) was developed to enhance the bioavailability of Ori. The effect of ligand (biotin) modification on oral absorption of Ori encapsulated in NLCs was also explored. Ori-loaded NLCs (Ori–NLCs) were prepared by the melt dispersion-high pressure homogenization method. Biotin modification of Ori–NLCs was achieved by EDC and NHS in aqueous phase. The obtained biotin-decorated Ori–NLCs (Bio-Ori–NLCs) were 144.9   nm in size with an entrapment efficiency of 49.54% and a drug load of 4.81%. Oral bioavailability was enhanced by use of Bio-Ori–NLCs with a relative bioavailability of 171.01%, while the value of non-modified Ori–NLCs was improved to 143.48%. Intestinal perfusion showed that Ori solution unexpectedly exhibited a moderate permeability, indicating that permeability was not a limiting factor of Ori absorption. Ori could be rapidly metabolized that was the main cause of low bioavailability. However, there was a difference in the enhancement of bioavailability between Bio-Ori–NLCs and conventional NLCs. Although severe lipolyses happened both on Bio-Ori–NLCs and non-modified NLCs, the performance of Bio-Ori–NLCs in the bioavailability improvement was more significant. Overall, Bio-Ori–NLCs can further promote the oral absorption of Ori by a ligand-mediated active transport. It may be a promising carrier for the oral delivery of Ori.

Oridonin-induced ferroptosis potentiates cancer immunotherapy

Xiangyu Jin,Didi Liu,Yitan Su,Ting Xue,Tengchuan Jin,Yi Huang

We identify oridonin induces ferroptosis through high throughput screening. • We found oridonin covalently binds to cysteine to block glutathione synthesis via its α, β-unsaturated carbonyl group. • We developed a tumor-targeting and hypoxia-responsive nanoparticle platform to deliver oridonin to achieve specific induction of tumor cells ferroptosis in vivo. • We found oridonin inhibits tumor growth and enhances antitumor immunity in various animal tumor models of colorectal cancer transplants and metastases. Ferroptosis, an iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxidation and iron, has emerged as a compelling vulnerability for cancer therapy. However, the scarcity of potent ferroptosis inducers with favorable pharmacological properties and their limited ability to reshape the immunosuppressive tumor microenvironment (TME) remain significant challenges. Here, we identify Oridonin (Ori), the major active component of the traditional Chinese medicine Rabdosia rubescens , as a novel and potent ferroptosis inducer through high-throughput screening (HTS). Mechanistically, we reveal that Ori covalently binds to cysteine to impair glutathione (GSH) biosynthesis, thereby triggering lipid peroxidation and ferroptosis. Notably, the α, β-unsaturated carbonyl group within Ori is identified as the critical pharmacophore for the ferroptosis-inducing effect. Considering that the therapeutic efficacy of Ori in vivo is greatly limited by its poor water solubility and tumor targeting ability, we engineer a tumor-targeting and hypoxia-responsive nanoparticle platform to deliver Ori (Ori-NP) to enable precise intratumoral release. Our results demonstrate that Ori-NP effectively suppresses tumor progression by inducing tumor cells ferroptosis mediated by ACSL4. Beyond direct cytotoxicity, Ori-NP serves as a potent immunomodulator that remodels the immunosuppressive TME by promoting dendritic cell maturation and enhancing CD8 + T cell infiltration. Consequently, the combination of Ori-NP with anti-PD-1 antibodies yields a potent synergistic antitumor effect. Overall, our research provides a powerful therapeutic strategy to harness ferroptosis for synergistic cancer immunotherapy.

Oridonin interferes with simple steatosis of liver cells by regulating autophagy

Boning Cheng,Jianhong Jin,Dianlei Liu,Tingting Shi,Xiaoqing Fu,Chuntao Liu,Shourong Liu,Rui Wu

Oridonin has significant liver-protective effects, but its effect on liver steatosis has not been reported. We investigated the effects of oridonin on liver steatosis by cell cultures. The optimal experimental concentration of oridonin was determined through cytotoxicity experiments. A simple steatosis liver cell model was induced using free fatty acids (FFA). After adding oridonin to the FFA-induced cell model for 24 h, the lipid droplets and triglyceride (TG) content in the cells were measured by Oil Red O staining and TG kits. The expressions of autophagy-related markers (cyclin dependent kinases inhibitor 1a (p21), Beclin-1, microtubule-associated protein light chain 3 (LC3)-I and LC3-II, protein kinase B (AKT), phosphorylated-AKT (p-AKT), AMP-activated protein kinase (AMPK), and phosphorylated-AMPK (p-AMPK)) were detected by Western blot. Based on the results, the cell model was further treated by autophagy inhibitor 3-methyladenine (3-MA) to determine the degree of steatosis and the expressions of autophagy-related factors. Oridonin at a concentration higher than 10 μmol/L caused cytotoxicity to the cells. Adding 10 μmol/L oridonin to the FFA-induced cell model effectively reduced lipid droplets and TG content in the cells. Oridonin up-regulated p21, Beclin-1 and LC3-II expressions, but down-regulated those of p62 and LC3-I. Also, oridonin increased the ratios of LC3-II/LC3-I and p-AMPK/AMPK, but reduced that of p-AKT/AKT. With the addition of 3-MA, the effect of oridonin on reducing steatosis was partially reversed, and the autophagy was inhibited. This study found that oridonin can activate autophagy, thereby preventing simple steatosis of liver cells.

Oridonin Loaded Peptide Nanovesicles Alleviate Nonalcoholic Fatty Liver Disease in Mice

Lifen Zhang,Yao Yu,Qi Wang,Xi Huang,Zheng Feng,Zhi Li

This study was to construct a nanovesicle delivery system to improve the loading efficiency and stability of ORI for the treatment of nonalcoholic fatty liver disease (NAFLD). This nanovesicles (NVs) exerted a narrow size distribution (195.6 ± 11.49 nm) and high entrapment efficiency (84.46 ± 1.34%). In vitro cell studies demonstrated that the NVs treatment enhanced the cellular uptake of ORI and reduced lipid over-accumulation and total cholesterol levels in NAFLD cell model. At the same time, in vivo study proved that, compared with the normal group, the model group mice showed a decrease in body weight, a significant increase in liver index (6.71 ± 0.62, p < 0.01), and symptoms of liver lipid accumulation, lipid vesicles, and liver tissue fibrosis. Compared with the model group, after high-dose ORI NVs intervention, mice gained weight, decreased liver index (4.69 ± 0.55, p < 0.01), reduced hepatic lipid droplet vacuoles, reduced lipid accumulation (reduced oil red area, p < 0.001), and alleviated the degree of liver fibrosis (reduced blue collagen area, p < 0.001). In conclusion, ORI/HP-β-CD/H9-HePC NVs showed specific liver accumulation and improved therapeutic effects, the nano drug loading system provides a promising strategy for the encapsulation of ORI to effectively alleviate the process of NAFLD.

Oridonin suppresses autophagy and survival in rheumatoid arthritis fibroblast-like synoviocytes

Shou-Di He,Sheng-Guang Huang,Hui-Jun Zhu,Xiao-Guang Luo,Kang-Han Liao,Jie-Yao Zhang,Ning Tan,De-Yu Li

Context Oridonin exhibits various pharmacological and physiological activities, including antioxidant, antibacterial, anti-inflammatory, pro-apoptotic, anticancer and neurological effects. However, its role in rheumatoid arthritis (RA) is yet to be revealed.Objective We evaluated the effects of oridonin on the survival and autophagy of RA-fibroblast-like synoviocytes (FLSs).Materials and methods RA-FLSs were treated with oridonin at serial concentrations of 0, 2, 4, 6, 8 and 10 µg/mL for 24, 48 and 72 h. Then, cell proliferation and apoptosis were measured. A GFP-LC3 plasmid was transfected into the cells to determine autophagy.Results Oridonin suppressed RA-FLS proliferation in a dose-dependent manner. The half maximal inhibitory concentrations (IC50) of oridonin at 24, 48 and 72 h were 8.28, 7.88 and 8.35 µg/mL, respectively. Treatment with oridonin for 24 h increased apoptosis by 4.1%, and increased the protein levels of Bax and cleaved caspase-3 but significantly decreased the levels of IL-1β in the culture supernatant (p < 0.05). In addition, 6 h of oridonin treatment significantly decreased the number of GFP-LC3 punctate dots and inhibited the protein levels of ATG5 and Beclin1 by 80.01% and 42.12%, respectively. Chloroquine (CQ) significantly reinforced the effects of oridonin on inhibition of autophagy, suppression of proliferation, and induction of apoptosis in RA-FLSs (p < 0.05).Conclusions Our results indicate that treatment with oridonin in combination with CQ inhibits autophagy and cell proliferation and induces apoptosis in RA-FLSs more effectively than treatment oridonin alone. This finding indicates that oridonin is a potential therapeutic agent for RA.

Mitochondrial ROS contribute to oridonin-induced HepG2 apoptosis through PARP activation

Xiaoning Liu,Jingjing Kang,Hui Wang,Tao Huang

Oridonin, the main active constituent of Rabdosia rubescens, is known to exert antitumor activity via the induction of apoptosis in numerous types of human cancer cells. However, the underlying regulatory mechanisms of mitochondrial ROS in oridonin‑induced HepG2 apoptosis remain largely unknown, due to limitations of subcellular imaging resolution. Previously, it has been suggested that mitochondria serve a potential role in sensing and signaling cellular redox changes in vital biological processes such as cell death and the abiotic stress response, based on studies involving the mitochondrial‑targeted redox‑sensitive green fluorescent protein (GFP). To address this, a mitochondrial‑targeted Grx1‑roGFP2 (mtGrx1‑roGFP2) biosensor was implemented to monitor real‑time mitochondrial redox changes of HepG2 cells in response to either H2O2/DTT or oridonin/SS31 treatment. It was determined that oridonin caused a perturbation in mitochondrial redox status, which in turn contributed to oridonin‑induced apoptosis. Furthermore, a novel mechanism underlying the regulation of mitochondrial redox changes in oridonin‑induced HepG2 apoptosis, presumably dependent on PARP cleavage, was proposed. In conclusion, the present study provides evidence in support of mitochondrial redox changes as a potential mediator in the apoptotic activities of oridonin in HepG2 cells, which provides insight into the molecular mechanisms by which mitochondrial redox signaling regulates oridonin‑induced apoptosis in cancer therapy, and the development of mitochondria‑specific oridonin as a promising novel anticancer therapeutic strategy.

Synthesis, characterization, in vitro and in vivo evaluation of PEGylated oridonin conjugates

Jingyi Shen,Dianrui Zhang,Zhongxi Zhao,Lejiao Jia,Dandan Zheng,Guangpu Liu,Leilei Hao,Qiang Zhang,Xiaona Tian,Caiyun Li,Hejian Guo

Oridonin (ORI), a diterpenoid compound with promising antitumor activity , was proved to possess potent antileukemia efficacies in vitro and in vivo recently. However, the development and application of ORI was limited by its poor solubility and rapid plasma clearance. The purpose of this study was to solve these problems. PEGylated oridonin linked with succinic acid (SA) as spacer moiety (PEG-SA-ORI conjugate) was synthesized. mPEG amines with four specifications of molecular weight (MW) were utilized. All polymeric conjugates showed satisfactory aqueous solubility and in vitro studies implied that the drug solubility and release features of conjugates were relevant to PEGs. The drug solubility increased more when the MW of PEG was lower, while more significant sustained-release effect was shown with higher PEG MW. Moreover, the release behaviors of conjugates showed a pH-sensitive property. In vivo pharmacokinetic studies demonstrated that the elimination half-life was prolonged in comparison with ORI solution. PEGylation could be a promising method to obtain better efficacy in the field of drug delivery system .

Oridonin‐Loaded PDA@Gel@GO Nanocapsules Modulate NLRP3 and Epithelial Repair in Colitis

Wenbo Yuan,Qirui Zhao,Jing Hua,Lingyao Xu,Yufan Wang,Tongtong Xu,Zuchao Du,Liping Wu,Daxiang Cui

Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by sustained mucosal inflammation and epithelial barrier dysfunction, closely associated with aberrant NOD‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome activation. Targeted oral therapies that simultaneously suppress inflammation and promote mucosal repair remain limited. We developed an orally administrable nanomicrocapsule system (PDA@Gel@GO) for colon‐targeted delivery of oridonin, a natural diterpenoid with anti‐inflammatory activity. The system was constructed by encapsulating galactosylated carboxymethyl chitosan–based oridonin nanomicelles (GO) within gelatin microspheres, followed by polydopamine coating to enhance gastrointestinal stability and mucosal adhesion. In a dextran sulfate sodium (DSS)‐induced UC mouse model, PDA@Gel@GO exhibited preferential accumulation in inflamed colonic tissues and significantly improved body weight loss, disease activity index, and colon shortening. Mechanistic studies demonstrated that PDA@Gel@GO treatment suppressed NLRP3 inflammasome activation, as evidenced by reduced expression of NLRP3, ASC, caspase‐1, and IL‐1β, accompanied by attenuation of oxidative stress and restoration of intestinal barrier proteins. Transcriptomic analysis further revealed activation of gene programs associated with epithelial regeneration, cell cycle progression, and DNA repair, suggesting coordinated inflammation resolution and mucosal repair. Collectively, this study presents a macrophage‐targeted, multilayered nanomicrocapsule platform that enhances the therapeutic efficacy of oridonin through precise colon targeting and integrated anti‐inflammatory and tissue‐protective effects, providing a promising strategy for precision treatment of UC. Mechanism of galactosylated carboxymethyl chitosan nanomicelle oral microcapsules delivering oridonin in alleviating colitis via targeting the NLRP3 inflammasome.

Preparation, characterization, and anti-colon cancer activity of oridonin-loaded long-circulating liposomes

Chunxiao Gao,Liang Zhang,Zhan Tang,Zhengyu Fang,Xiaoli Ye,Wenying Yu