Hepatosteatosis is characterized by abnormal accumulation of triglycerides(TG),leading to prolonged and chronic inflammatory infiltration.To date,there is still a lack of effective and economical therapies for hepatos...Hepatosteatosis is characterized by abnormal accumulation of triglycerides(TG),leading to prolonged and chronic inflammatory infiltration.To date,there is still a lack of effective and economical therapies for hepatosteatosis.Oridonin(ORI)is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens.In this paper,we showed that ORI exerted significant protective effects against hepatic steatosis,inflammation and fibrosis,which was dependent on LXRa signaling.It is reported that LXRa regulated lipid homeostasis between triglyceride(TG)and phosphatidylethanolamine(PE)by promoting ATGL and EPT1 expression.Therefore,we implemented the lipidomic strategy and luciferase reporter assay to verify that ORI contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRadependent manner,and the results showed the TG reduction and PE elevation.In detail,hepatic TG overload and lipotoxicity were reversed after ORI treatment by modulating the ATGL and EPT1 genes,respectively.Taken together,the data provide mechanistic insights to explain the bioactivity of ORI in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRa-ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders.展开更多
AIM:To investigate the effect of oridonin on nuclear transcription factors and to study the relationship between biological behavior and inflammatory factors in human pancreatic cancer(BxPC-3)cells.METHODS:BxPC-3 cell...AIM:To investigate the effect of oridonin on nuclear transcription factors and to study the relationship between biological behavior and inflammatory factors in human pancreatic cancer(BxPC-3)cells.METHODS:BxPC-3 cells were treated with various concentrations of oridonin,and viability curves were generated to test for inhibitory effects of the drug on cells.The expression of cytokines such as interleukin-1β(IL-1β),IL-6,or IL-33 was detected in BxPC-3 cell supernatants using an enzyme-linked immunosorbent assay(ELISA),and the protein expression of nuclear transcription factors including nuclear factorκB,activating protein-1,signal transducer and activator of transcription 3,bone morphogenetic protein 2,trans-forming growth factorβ1 and sma and mad homologues in BxPC-3 cells was detected using Western blot.Carcinoma hallmark-related proteins such as survivin,vascular endothelial growth factor,and matrix metallopeptidase 2 were also detected using immunoblotting,and intra-nuclear IL-33 expression was detected using immunofluorescent staining.RESULTS:Treatment with oridonin reduced the viability of BxPC-3 cells in a dose dependent manner.The cells exhibited reduced growth following treatment with 8μg/mL oridonin(13.05%±3.21%,P<0.01),and the highest inhibitory ratio was 90.64%±0.70%,which was achieved with oridonin at a dose of32μg/mL.The IC50 value of oridonin in BxPC-3 cells was 19.32μg/mL.ELISA analysis revealed that oridonin down-regulated the inflammatory factors IL-1β,IL-6,and IL-33 in a dose-dependent manner.IL-1βexpression was significantly reduced in the 16 and 32μg/mL treatment groups compared to the control group(12.97±0.45 pg/mL,11.17±0.63 pg/mL vs 14.40±0.38pg/mL,P<0.01).Similar trends were observed for IL-6expression,which was significantly reduced in the 16and 32μg/mL treatment groups compared to the control group(4.05±0.14 pg/mL vs 4.45±0.43 pg/mL,P<0.05;3.95±0.13 pg/mL vs 4.45±0.43 pg/mL,P<0.01).IL-33 expression was significantly reduced in the8,16,and 32μg/mL treatment groups compared to the control group(911.05±14.18 pg/mL vs 945.25±12.09 pg/mL,P<0.05;802.70±11.88 pg/mL,768.54±10.98 pg/mL vs 945.25±12.09 pg/mL,P<0.01).Western blot and immunofluorescent staining analyses suggested that oridonin changed the hallmarks and regulated the expression of various nuclear transcription factors.CONCLUSION:The results obtained suggest that oridonin alters the hallmarks of pancreatic cancer cells through the regulation of nuclear transcription factors.展开更多
Objective: To investigate the therapeutic effect and the related mechanism of oridonin on mice with prostate cancer. Methods: Sixty BALB/C male nude mice were selected. A model of RM-1 cell transplantation tumor of pr...Objective: To investigate the therapeutic effect and the related mechanism of oridonin on mice with prostate cancer. Methods: Sixty BALB/C male nude mice were selected. A model of RM-1 cell transplantation tumor of prostate cancer was built by the subcutaneous inoculation of RM-1 cells. After that, those 60 experimental mice were randomly divided into groups A, B and C. Each group had 20 mice. Mice in group A were treated with 0.2 m L of normal saline(0.9%) by intraperitoneal injection once a day; mice in group B received intraperitoneal injection of 1.875 mg/m L of oridonin once a day; and mice in group C received intraperitoneal injection of 7.5 mg/m L of oridonin once a day. Mice in the three groups were treated uninterruptedly for 5 weeks and were all killed. Then, tumors were excised and weighed to calculate their growth inhibitory rate, volume increment and anti-tumor rate. Thymus and spleen of mice in the three groups were collected to calculate the thymus and spleen index. Immunohistochemical staining was applied to observe the expression of caspase-3 in prostate cancer tissue of mice of the three groups. Results: The qualities and volume increment of tumors in groups B and C were significantly lower than those of group A(P < 0.05); the qualities and volume increment of tumors in groups C were evidently lower than those of group B(P < 0.05); the tumor volume increment and anti-tumor rate in group C were obviously higher than those of group B(P < 0.05); the thymus and spleen indexes of groups B and C were distinctly higher than those of group A(P < 0.05); comparison of the thymus and spleen indexes between group B and group C showed no statistical differences(P > 0.05). Immumohistochemical staining revealed that the caspase-3 protein in prostate cancer tissue of mice of group A expressed negatively with colourless or light-colored karyon; while the caspase-3 protein in prostate cancer tissue of mice of group B expressed positively with dark-colored karyon, centralized distribution and granular sensation; and the caspase-3 in prostate cancer tissue of mice of group C showed strong positive expression with big and darker colored karyon and dense distribution. Conclusions: Oridonin can inhibit the growth of RM-1 prostate cancer cells effectively and have great therapeutic effects on RM-1 cell transplantation tumor of prostate cancer.展开更多
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 ...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 highquality oridonin.Static absorption kinetics,thermodynamic and dynamic adsorption were evaluated.HP20 was selected for further study due to its high adsorption capacity of 32 mgg 1 and desorption ratio with 98.5%.The pseudosecondorder 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 HP20 provides an efficient method to purify most oridonin from R.rubescens.展开更多
The phase sensitive NOESY spectrum of oridonin was treated using Full Relaxation Matrix Analysis(FRMA) approach, and the cross relaxation rates of proton pairs were obtained by diagonalizing the NOE matrix of oridonin...The phase sensitive NOESY spectrum of oridonin was treated using Full Relaxation Matrix Analysis(FRMA) approach, and the cross relaxation rates of proton pairs were obtained by diagonalizing the NOE matrix of oridonin. The inter proton distances were calculated according to 1/r6 ij ∝σij. The three-dimensional structure of oridonin in solution was calculated by the combination of WUPH, WUPH-S method with molecular mechanics minimization on the basis of NMR experiment.展开更多
AIM:To investigate the inhibitory effect of the combined use of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)and oridonin on choroidal melanoma cell lines,and to explore its underlying mechanism.METHO...AIM:To investigate the inhibitory effect of the combined use of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)and oridonin on choroidal melanoma cell lines,and to explore its underlying mechanism.METHODS:MUM-2B and C918 cells were treated with different concentrations of TRAIL and oridonin,and MTT assay used to evaluate the inhibition rate of the two compounds on cells.Then,the cell cycle distribution and apoptosis were detected by flow cytometry,and changes in apoptosis-related proteins such as death receptor 5(DR5),a-caspase-3,and x-linked inhibitor of apoptosis protein(XIAP)were detected by Western blot.MUM-2B cells were transfected with si-DR5,which interfered with the expression of the DR5 gene.MTT and Western blot assay were used to detect cell activity and apoptosis-related proteins.RESULTS:When TRAIL and oridonin were simultaneously administered to the MUM-2B cells,the apoptosis rate was significantly higher than that by the two drugs individually.However,the effect of combined use of TRAIL and oridonin on C918 cells was not significantly different from that used alone.Cell cycle analysis showed that TRAIL and oridonin could induce G2/M arrest in MUM-2B cells.The Western blot results showed that the protein expression levels of the DR5,a-caspase-3,and BAX increased,while the expression levels of the anti-apoptosis-related proteins XIAP and BCL-2 were suppressed when TRAIL and oridonin simultaneously administered to MUM-2B cells.Interfering the expression of DR5 gene in MUM-2B cells could reverse the inhibitory effect of oridonin and TRAIL on the proliferation and apoptosis induction of MUM-2B cells.CONCLUSION:The inhibitory effects of oridonin and TRAIL on MUM-2B cells are significantly enhanced when they were administered as a combined treatment,which may ascribe to up-regulation of DR5.展开更多
AIM:To investigate the effect and mechanism of oridonin on the gastric cancer cell line HGC-27 in vitro.METHODS:The inhibitory effect of oridonin on HGC-27 cells was detected using the 3-(4,5-dimethylthiazol2-yl)-2,5-...AIM:To investigate the effect and mechanism of oridonin on the gastric cancer cell line HGC-27 in vitro.METHODS:The inhibitory effect of oridonin on HGC-27 cells was detected using the 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyl tetrazolium bromide assay.After treatment with 10 μg/mL oridonin for 24 h and 48 h,the cells were stained with acridine orange/ethidium bromide.The morphologic changes were observed under an inverted fluorescence microscope.DNA fragmen-tation(a hallmark of apoptosis) and lactate dehydrogenase activity were examined using DNA ladder assay and lactate dehydrogenase-release assay.After treated with oridonin(0,1.25,2.5,5 and 10 μg/mL),HGC-27 cells were collected for anexin V-phycoerythrin and 7-amino-actinomycin D double staining and tested by flow cytometric analysis,and oridonin-induced apoptosis in HGC-27 cells was detected.After treatment with oridonin for 24 h,the effects of oridonin on expression of Apaf-1,Bcl-2,Bax,caspase-3 and cytochrome c were also analyzed using reverse-transcript polymerase chain reaction(RT-PCR) and Western blotting.RESULTS:Oridonin significantly inhibited the proliferation of HGC-27 cells in a dose-and time-dependent manner.The inhibition rates of HGC-27 treated with four different concentrations of oridonin for 24 h(1.25,2.5,5 and 10 μg/mL) were 1.78% ± 0.36%,4.96% ± 1.59%,10.35% ± 2.76% and 41.6% ± 4.29%,respectively,which showed a significant difference(P < 0.05).The inhibition rates of HGC-27 treated with oridonin at the four concentrations for 48 h were 14.77% ± 4.21%,21.57% ± 3.75%,30.31% ± 4.91% and 61.19% ± 5.81%,with a significant difference(P < 0.05).The inhibition rates of HGC-27 treated with oridonin for 72 h at the four concentrations were 25.77% ± 4.85%,31.86% ± 3.86%,48.30% ± 4.16% and 81.80% ± 6.72%,with a significant difference(P < 0.05).Cells treated with oridonin showed typical apoptotic features with acridine orange/ethidium bromide staining.After treatment with oridonin,the cells became round,shrank,and developed small buds around the nuclear membrane while forming apoptotic bodies.Lactate dehydrogenase(LDH) release assay showed that after treated with 1.25 μg/mL and 20 μg/mL oridonin for 24 h,LDH release of HGC-27 caused by apoptosis increased from 22.94% ± 3.8% to 52.68% ± 2.4%(P < 0.001).However,the change in the release of LDH caused by necrosis was insignificant,suggesting thatthe major cause of oridonin-induced HGC-27 cell death was apoptosis.Flow cytometric analysis also revealed that oridonin induced significant apoptosis compared with the controls(P < 0.05).And the apoptosis rates of HGC-27 induced by the four different concentrations of oridonin were 5.3% ± 1.02%,12.8% ± 2.53%,28.5% ± 4.23% and 49.6% ± 3.76%,which were in a dose-dependent manner(P < 0.05).After treatment for 24 h,DNA ladder showed that oridonin induced a significant increase in DNA fragmentation in a dosedependent manner.RT-PCR revealed that mRNA expression levels were up-regulated compared with the controls in caspase-3(0.917 ± 0.103 vs 0.357 ± 0.019,P < 0.05),cytochrome c(1.429 ± 0.111 vs 1.002 ± 0.014,P < 0.05),Apaf-1(0.688 ± 0.101 vs 0.242 ± 0.037,P < 0.05) and Bax(0.856 ± 0.101 vs 0.278 ± 0.027,P < 0.05)(P < 0.05),whereas down-regulated in Bcl-2(0.085 ± 0.012 vs 0.175 ± 0.030,P < 0.05).Western blotting analysis also confirmed this result.CONCLUSION:Apoptosis of HGC-27 induced by oridonin may be associated with differential expression of Apaf-1,caspase-3 and cytochrome c,which are highly dependent upon the mitochondrial pathway.展开更多
OBJECTIVE To study the inhibitory effect of oridonin on the growth of cancer cells. METHODS Fifteen human cancer cell lines were subjected to various concentrations of oridonin in culture medium. The inhibitory rate o...OBJECTIVE To study the inhibitory effect of oridonin on the growth of cancer cells. METHODS Fifteen human cancer cell lines were subjected to various concentrations of oridonin in culture medium. The inhibitory rate of cell growth was measured by the MTT assay, and compared with a negative con- trol and 5-Fu-positive control. RESULTS The 50% inhibiting concentration (IC50) and maximal inhibition (Imax) of oridonin shown by studying the growth of the cancer cell lines were as follows: leukemias (HL60 cells: 3.9 μg/ml and 73.8%, K562 cells: 4.3 μg/ml and 76.2%); esophageal cancers(SHEEC cells: 15.4 μg/ml and 99.2%, Eca109 cells: 15.1 μg/ml and 84.6%, TE1 cells: 4.0 μg/ml and 70.2%); gastric cancers (BGC823 cells: 7.6 μg/ml and 98.7%, SGC7901 cells: 12.3 μg/ml and 85.7%); colon cancers (HT29 cells: 13.6 μg/ml and 97.2%, HCT cells: 14.5 μg/ml and 96.5%); liver cancers (Bel7402 cells: 15.2 μg/ml and 89.2%, HepG2 cells: 7.1 μg/ml and 88.3%); pancreatic cancer (PC3 cells: 11.3 μg/ml and 68.4%); lung cancer (A549 cells: 18.6 μg/ml and 98.0% ); breast cancer (MCF7 cells: 18.4 μg/ml and 84.7%); uterine cervix cancer (Hela cells: 13.7 μg/ml and 98.5%). CONCLUSION Oridonin had a relatively wide anti-tumor spectrum, and a relatively strong inhibitory effect on the growth of the 15 human cancer cells. Inhibitory effects were concentration dependent.展开更多
ObjectiveTo investigate the anti-proliferation effect of oridonin on leukemic HL-60 cells and its mechanism. Methods HL-60 cells invitroin culture medium were given different concentrations of oridonin. The inhibitory...ObjectiveTo investigate the anti-proliferation effect of oridonin on leukemic HL-60 cells and its mechanism. Methods HL-60 cells invitroin culture medium were given different concentrations of oridonin. The inhibitory rate of cells were measured by microculture tetrazolium (MTT) assay, cell apoptotic rate was detected by flow cytometry (FCM),morphology of cell apoptosis was observed by hoechst 33258 fluorescence staining, and the activity of telomerase was det-ected using telomere repeat amplification protocol (TRAP) PCR-ELISA before and after apoptosis occurred. Results Oridonin could decrease telomerase activity, inhibit growth of HL-60 cells, and cause apoptosis significantly. The suppression was both in time- and dose-dependent manner. Marked morphological changes of cell apoptosis including condensation of chromatin and nuclear fragmentation were observed clearly by hoechst 33258 fluorescence staining especi-ally after cells were treated 48-60 hours by oridonin. Conclusions Oridonin has apparent anti-proliferation and apoptotic effects on HL-60 cells invitro, decreasing telomerase activity of HL-60 cells may be one of its most important mechanisms. These results will provide strong laboratory evidence of oridonin for clinical treatment of acute leukemia.展开更多
Objective: To investigate the effect of oridonin on proliferation and invasion of human multiple myeloma LP-1 cells and the underlying mechanism. Methods: LP-1 cells in culture medium in vitro were treated with oridon...Objective: To investigate the effect of oridonin on proliferation and invasion of human multiple myeloma LP-1 cells and the underlying mechanism. Methods: LP-1 cells in culture medium in vitro were treated with oridonin at the different concentration. Cell proliferation was measured by Microwave Theory and Techniques (MTT) assay and cell apoptotic rate was detected by flow cytometry. Morphology of cell apoptosis was observed by transmission electron microscope. Expressions of Bax, Bcl-2, Caspase-3, NF-κB as well as I-κB mRNA were detected by real-time PCR. Results: The MTT assays and flow cytometry revealed that oridonin could inhibit the growth of LP-1 cells and cause apoptosis significantly; the suppression was both in time- and dose-dependent manner. Marked morphological changes of cell apoptosis were found under a transmission electron microscope after the cells were treated with oridonin at 25 μmol/L for 24 h. Along with the apoptotic process, Bcl-2, Caspase-3,NF-κB gene expressions were down-regulated (P<0.05). On the contrast, the Bax and I-κB gene expressions were up-regulated (P<0.05). Conclusion: Oridonin could inhibit the proliferation of LP-1 cells via inducing apoptosis. We concluded that oridonin induces apoptosis in LP-1 cells via activation of caspase-3 as well as down-regulation of Bcl-2 and up-regulation of Bax expression. The results suggested that oridonin could induce apoptosis of LP-1 cells through mitochondria- and caspase3-dependent pathways. Meanwhile, the inhibition of NF-κB and the activation of I-κB indicate pro-apoptotic stimuli. In one word, oridonin might be an important potential anti-myeloma reagent.展开更多
The ent-kaurenoids(e.g.,oridonin and enmein)from the Isodon genus(Lamiaceae)are one class of diterpenoids with rich structural diversity and intriguing pharmaceutical activity.In contrast to the well-established gibbe...The ent-kaurenoids(e.g.,oridonin and enmein)from the Isodon genus(Lamiaceae)are one class of diterpenoids with rich structural diversity and intriguing pharmaceutical activity.In contrast to the well-established gibberellin pathway,oxidative modifications diversifying the ent-kaurene skeleton in Isodon have remained undetermined for half a century.Here we report a chromosome-level genome assembly of I.rubescens,a well-recognized oridonin producer long favored by Asian people as a traditional herb with antitumor effects.The shoot apex was confirmed to be the actual region actively producing ent-kaurene diterpenoids.Through comparative genomics and phylogenetic analyses,we discovered a cluster of tandem-duplicated CYP706V oxygenase-encoding genes located on an ancient genomic block widely distributed in eudicots,whereas almost exclusively emerged in Isodon plants.In the shoot apex,IrCYP706V2 and IrCYP706V7 oxidized the ent-kaurene core in the initial stage of oridonin biosynthesis.Loss of CYP706Vs in other Lamiaceae plants offered an explanation for the specific kaurenoid production in Isodon plants.Moreover,we found that the Isodon genomes encode multiple diterpenoid synthases that are potentially involved in generating diterpenoid diversity.These findings provided new insights into the evolution of the lineage-specific diterpenoid pathway and laid a foundation for improving production of bioactive ent-kaurene-type diterpenoids by molecular breeding and synthetic biology approaches.展开更多
COVID-19 has become a global public health crisis since its outbreak in China in December 2019.Currently there are few clinically effective drugs to combat SARS-CoV-2 infection.The main protein(M^(pro)),papain-like pr...COVID-19 has become a global public health crisis since its outbreak in China in December 2019.Currently there are few clinically effective drugs to combat SARS-CoV-2 infection.The main protein(M^(pro)),papain-like protease(PL^(pro))and RNA-dependent RNA polymerase(RdRp)of SARS-CoV-2 are involved in the viral replication,and might be prospective targets for anti-coronavirus drug development.Here,we investigated the antiviral activity of oridonin,a natural small-molecule compound,against SARS-CoV-2 infection in vitro.The time-of-addition analysis showed that oridonin efficiently inhibited SARS-CoV-2 infection by interfering with the genome replication at the post-entry stage.Mechanistically,the inhibition of viral replication by oridonin depends on the oxidation activity ofα,β-unsaturated carbonyl.Further experiments showed that oridonin not only effectively inhibited SARS-CoV-2 Mpro activity,but also had some inhibitory effects on PLpro-mediated deubiquitinating and viral polymerase-catalyzed RNA elongation activities at high concentrations.In particular,oridonin could inhibit the bat SARS-like CoV and the newly emerged SARS-CoV-2 omicron variants(BA.1 and BA.2),which highlights its potential as a pan-coronavirus antiviral agent.Overall,our data provide strong evidence that oridonin is an efficient antiviral agent against SARS-CoV-2 infection.展开更多
Non-small cell lung cancer(NSCLC) accounts for about 85% of all lung cancers. Traditional chemotherapy for this disease leads to serious side effects. Here we prepared an inhalable oridonin-loaded poly(lactic-co-glyco...Non-small cell lung cancer(NSCLC) accounts for about 85% of all lung cancers. Traditional chemotherapy for this disease leads to serious side effects. Here we prepared an inhalable oridonin-loaded poly(lactic-co-glycolic)acid(PLGA) large porous microparticle(LPMP) for in situ treatment of NSCLC with the emulsion/solvent evaporation/freeze-drying method. The LPMPs were smooth spheres with many internal pores. Despite a geometric diameter of 10 mm, the aerodynamic diameter of the spheres was only 2.72 mm, leading to highly efficient lung deposition. In vitro studies showed that most of oridonin was released after 1 h, whereas the alveolar macrophage uptake of LPMPs occurred after 8 h, so that most of oridonin would enter the surroundings without undergoing phagocytosis. Rat primary NSCLC models were built and administered with saline, oridonin powder, gemcitabine, and oridonin-loaded LPMPs via airway, respectively. The LPMPs showed strong anticancer effects. Oridonin showed strong angiogenesis inhibition and apoptosis. Relevant mechanisms are thought to include oridonin-induced mitochondrial dysfunction accompanied by low mitochondrial membrane potentials, downregulation of BCL-2 expressions, upregulation of expressions of BAX, caspase-3 and caspase-9. The oridonin-loaded PLGALPMPs showed high anti-NSCLC effects after pulmonary delivery. In conclusion, LPMPs are promising dry powder inhalations for in situ treatment of lung cancer.展开更多
Collaboration of c-KIT mutations with AML1-ETO (AE) has been demonstrated to induce t(8;21) acute myeloid leukemia (AML).Targeted therapies designed to eliminate AE and c-KIT oncoproteins may facilitate effective trea...Collaboration of c-KIT mutations with AML1-ETO (AE) has been demonstrated to induce t(8;21) acute myeloid leukemia (AML).Targeted therapies designed to eliminate AE and c-KIT oncoproteins may facilitate effective treatment of t(8;21) AML.Homoharringtonine (HHT) features activity against tumor cells harboring c-KIT mutations,whereas oridonin can induce t(8;21) AML cell apoptosis and AE cleavage.Therefore,studies should explore the efficacy of combination therapy with oridonin and HHT in t(8;21) AML.In this study,we investigated the synergistic effects and mechanism of oridonin combined with HHT in t(8;21) AML cell line and mouse model.The two drugs synergistically inhibited cell viability and induced significant mitochondrial membrane potential loss and apoptosis.Oridonin and HHT induced significant downregulation of c-KIT and its downstream signaling pathways and promoted AE cleavage.HHT increased intracellular oridonin concentration by modulating the expressions of MRP1 and MDR1,thus enhancing the effects of oridonin.The combination of oridonin and HHT prolonged t(8;21) leukemia mouse survival.In conclusion,oridonin and HHT exert synergistic effects against t(8;21) leukemia in vivo and in vitro,thereby indicating that their combination may be an effective therapy for t(8;21) leukemia.展开更多
Cancer is one of the diseases with high morbidity and mortality on a global scale.Chemotherapy remains the primary treatment option for most cancer patients,including patients with progressive,metastatic,and recurrent...Cancer is one of the diseases with high morbidity and mortality on a global scale.Chemotherapy remains the primary treatment option for most cancer patients,including patients with progressive,metastatic,and recurrent diseases.To date,hundreds of chemotherapy drugs are used to treat various cancers,however,the anti-cancer eficacy and outcomes are largely hampered by chemotherapy-associated toxicity and acquired therapeutic resistance.The natural product(NP)oridonin has been extensively studied for its anti-cancer efficacy.More recently,oridonin has been shown to overcome drug resistance through multiple mechanisms,with yet-to-be-defined bona fide targets.Hundreds of oridonin derivative analogs(oridonalogs)have been synthesized and screened for improved potency,bioavailability,and other drug properties.Particularly,many of these oridonalogs have been tested against oridonin for tumor growth inhibition,potential for overcoming therapeutic resistance,and immunity modulation.This concise review seeks to summarize the advances in this field in light of identifying clinical-trial level drug candidates with the promise for treating progressive cancers and reversing chemoresistance.展开更多
Oridonin,a diterpenoid isolated from Rabdosia rubescens(Hemsl.)Hara,has been proved to possess remarkable anticancer activity,in addition to its potential in antiinflammation and antibacteria.The purpose of this artic...Oridonin,a diterpenoid isolated from Rabdosia rubescens(Hemsl.)Hara,has been proved to possess remarkable anticancer activity,in addition to its potential in antiinflammation and antibacteria.The purpose of this article is to review current progress in oridonin concerned about a relationship between the chemical structure/modifications and its anticancer activity and to discuss the molecular mechanisms underlying its anticancer activity,such as suppression of tumor proliferation and induction of tumor cell death,and the cell signal transduction in anticancer activity of oridonin.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:81973388)Marine Economy Development Project of Guangdong Province(Project No.:GDNRC[2021]52)the Key Research and Development Program of Guangdong Province(Program No.:2020B1111030005).
文摘Hepatosteatosis is characterized by abnormal accumulation of triglycerides(TG),leading to prolonged and chronic inflammatory infiltration.To date,there is still a lack of effective and economical therapies for hepatosteatosis.Oridonin(ORI)is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens.In this paper,we showed that ORI exerted significant protective effects against hepatic steatosis,inflammation and fibrosis,which was dependent on LXRa signaling.It is reported that LXRa regulated lipid homeostasis between triglyceride(TG)and phosphatidylethanolamine(PE)by promoting ATGL and EPT1 expression.Therefore,we implemented the lipidomic strategy and luciferase reporter assay to verify that ORI contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRadependent manner,and the results showed the TG reduction and PE elevation.In detail,hepatic TG overload and lipotoxicity were reversed after ORI treatment by modulating the ATGL and EPT1 genes,respectively.Taken together,the data provide mechanistic insights to explain the bioactivity of ORI in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRa-ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders.
基金Supported by The Qianjiang Talent Project of Zhejiang Province,No.2013R10072the Natural Science Foundation of Zhejiang Province,Nos.LY14H160037 and LY12H16007
文摘AIM:To investigate the effect of oridonin on nuclear transcription factors and to study the relationship between biological behavior and inflammatory factors in human pancreatic cancer(BxPC-3)cells.METHODS:BxPC-3 cells were treated with various concentrations of oridonin,and viability curves were generated to test for inhibitory effects of the drug on cells.The expression of cytokines such as interleukin-1β(IL-1β),IL-6,or IL-33 was detected in BxPC-3 cell supernatants using an enzyme-linked immunosorbent assay(ELISA),and the protein expression of nuclear transcription factors including nuclear factorκB,activating protein-1,signal transducer and activator of transcription 3,bone morphogenetic protein 2,trans-forming growth factorβ1 and sma and mad homologues in BxPC-3 cells was detected using Western blot.Carcinoma hallmark-related proteins such as survivin,vascular endothelial growth factor,and matrix metallopeptidase 2 were also detected using immunoblotting,and intra-nuclear IL-33 expression was detected using immunofluorescent staining.RESULTS:Treatment with oridonin reduced the viability of BxPC-3 cells in a dose dependent manner.The cells exhibited reduced growth following treatment with 8μg/mL oridonin(13.05%±3.21%,P<0.01),and the highest inhibitory ratio was 90.64%±0.70%,which was achieved with oridonin at a dose of32μg/mL.The IC50 value of oridonin in BxPC-3 cells was 19.32μg/mL.ELISA analysis revealed that oridonin down-regulated the inflammatory factors IL-1β,IL-6,and IL-33 in a dose-dependent manner.IL-1βexpression was significantly reduced in the 16 and 32μg/mL treatment groups compared to the control group(12.97±0.45 pg/mL,11.17±0.63 pg/mL vs 14.40±0.38pg/mL,P<0.01).Similar trends were observed for IL-6expression,which was significantly reduced in the 16and 32μg/mL treatment groups compared to the control group(4.05±0.14 pg/mL vs 4.45±0.43 pg/mL,P<0.05;3.95±0.13 pg/mL vs 4.45±0.43 pg/mL,P<0.01).IL-33 expression was significantly reduced in the8,16,and 32μg/mL treatment groups compared to the control group(911.05±14.18 pg/mL vs 945.25±12.09 pg/mL,P<0.05;802.70±11.88 pg/mL,768.54±10.98 pg/mL vs 945.25±12.09 pg/mL,P<0.01).Western blot and immunofluorescent staining analyses suggested that oridonin changed the hallmarks and regulated the expression of various nuclear transcription factors.CONCLUSION:The results obtained suggest that oridonin alters the hallmarks of pancreatic cancer cells through the regulation of nuclear transcription factors.
基金supported by the National Natural Science Foundation with the number of 30700875/C03030310
文摘Objective: To investigate the therapeutic effect and the related mechanism of oridonin on mice with prostate cancer. Methods: Sixty BALB/C male nude mice were selected. A model of RM-1 cell transplantation tumor of prostate cancer was built by the subcutaneous inoculation of RM-1 cells. After that, those 60 experimental mice were randomly divided into groups A, B and C. Each group had 20 mice. Mice in group A were treated with 0.2 m L of normal saline(0.9%) by intraperitoneal injection once a day; mice in group B received intraperitoneal injection of 1.875 mg/m L of oridonin once a day; and mice in group C received intraperitoneal injection of 7.5 mg/m L of oridonin once a day. Mice in the three groups were treated uninterruptedly for 5 weeks and were all killed. Then, tumors were excised and weighed to calculate their growth inhibitory rate, volume increment and anti-tumor rate. Thymus and spleen of mice in the three groups were collected to calculate the thymus and spleen index. Immunohistochemical staining was applied to observe the expression of caspase-3 in prostate cancer tissue of mice of the three groups. Results: The qualities and volume increment of tumors in groups B and C were significantly lower than those of group A(P < 0.05); the qualities and volume increment of tumors in groups C were evidently lower than those of group B(P < 0.05); the tumor volume increment and anti-tumor rate in group C were obviously higher than those of group B(P < 0.05); the thymus and spleen indexes of groups B and C were distinctly higher than those of group A(P < 0.05); comparison of the thymus and spleen indexes between group B and group C showed no statistical differences(P > 0.05). Immumohistochemical staining revealed that the caspase-3 protein in prostate cancer tissue of mice of group A expressed negatively with colourless or light-colored karyon; while the caspase-3 protein in prostate cancer tissue of mice of group B expressed positively with dark-colored karyon, centralized distribution and granular sensation; and the caspase-3 in prostate cancer tissue of mice of group C showed strong positive expression with big and darker colored karyon and dense distribution. Conclusions: Oridonin can inhibit the growth of RM-1 prostate cancer cells effectively and have great therapeutic effects on RM-1 cell transplantation tumor of prostate cancer.
基金the National Natural Science Foundation of China(21676145)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD,China).
文摘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 highquality oridonin.Static absorption kinetics,thermodynamic and dynamic adsorption were evaluated.HP20 was selected for further study due to its high adsorption capacity of 32 mgg 1 and desorption ratio with 98.5%.The pseudosecondorder 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 HP20 provides an efficient method to purify most oridonin from R.rubescens.
基金Supported by the National Natural Science Foundation of China
文摘The phase sensitive NOESY spectrum of oridonin was treated using Full Relaxation Matrix Analysis(FRMA) approach, and the cross relaxation rates of proton pairs were obtained by diagonalizing the NOE matrix of oridonin. The inter proton distances were calculated according to 1/r6 ij ∝σij. The three-dimensional structure of oridonin in solution was calculated by the combination of WUPH, WUPH-S method with molecular mechanics minimization on the basis of NMR experiment.
基金Ningbo Leader and Top Notch Person Training Project(No.20150012).
文摘AIM:To investigate the inhibitory effect of the combined use of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)and oridonin on choroidal melanoma cell lines,and to explore its underlying mechanism.METHODS:MUM-2B and C918 cells were treated with different concentrations of TRAIL and oridonin,and MTT assay used to evaluate the inhibition rate of the two compounds on cells.Then,the cell cycle distribution and apoptosis were detected by flow cytometry,and changes in apoptosis-related proteins such as death receptor 5(DR5),a-caspase-3,and x-linked inhibitor of apoptosis protein(XIAP)were detected by Western blot.MUM-2B cells were transfected with si-DR5,which interfered with the expression of the DR5 gene.MTT and Western blot assay were used to detect cell activity and apoptosis-related proteins.RESULTS:When TRAIL and oridonin were simultaneously administered to the MUM-2B cells,the apoptosis rate was significantly higher than that by the two drugs individually.However,the effect of combined use of TRAIL and oridonin on C918 cells was not significantly different from that used alone.Cell cycle analysis showed that TRAIL and oridonin could induce G2/M arrest in MUM-2B cells.The Western blot results showed that the protein expression levels of the DR5,a-caspase-3,and BAX increased,while the expression levels of the anti-apoptosis-related proteins XIAP and BCL-2 were suppressed when TRAIL and oridonin simultaneously administered to MUM-2B cells.Interfering the expression of DR5 gene in MUM-2B cells could reverse the inhibitory effect of oridonin and TRAIL on the proliferation and apoptosis induction of MUM-2B cells.CONCLUSION:The inhibitory effects of oridonin and TRAIL on MUM-2B cells are significantly enhanced when they were administered as a combined treatment,which may ascribe to up-regulation of DR5.
基金Supported by Medical and Health Research Foundation of Zhejiang Province,No. 2009B019
文摘AIM:To investigate the effect and mechanism of oridonin on the gastric cancer cell line HGC-27 in vitro.METHODS:The inhibitory effect of oridonin on HGC-27 cells was detected using the 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyl tetrazolium bromide assay.After treatment with 10 μg/mL oridonin for 24 h and 48 h,the cells were stained with acridine orange/ethidium bromide.The morphologic changes were observed under an inverted fluorescence microscope.DNA fragmen-tation(a hallmark of apoptosis) and lactate dehydrogenase activity were examined using DNA ladder assay and lactate dehydrogenase-release assay.After treated with oridonin(0,1.25,2.5,5 and 10 μg/mL),HGC-27 cells were collected for anexin V-phycoerythrin and 7-amino-actinomycin D double staining and tested by flow cytometric analysis,and oridonin-induced apoptosis in HGC-27 cells was detected.After treatment with oridonin for 24 h,the effects of oridonin on expression of Apaf-1,Bcl-2,Bax,caspase-3 and cytochrome c were also analyzed using reverse-transcript polymerase chain reaction(RT-PCR) and Western blotting.RESULTS:Oridonin significantly inhibited the proliferation of HGC-27 cells in a dose-and time-dependent manner.The inhibition rates of HGC-27 treated with four different concentrations of oridonin for 24 h(1.25,2.5,5 and 10 μg/mL) were 1.78% ± 0.36%,4.96% ± 1.59%,10.35% ± 2.76% and 41.6% ± 4.29%,respectively,which showed a significant difference(P < 0.05).The inhibition rates of HGC-27 treated with oridonin at the four concentrations for 48 h were 14.77% ± 4.21%,21.57% ± 3.75%,30.31% ± 4.91% and 61.19% ± 5.81%,with a significant difference(P < 0.05).The inhibition rates of HGC-27 treated with oridonin for 72 h at the four concentrations were 25.77% ± 4.85%,31.86% ± 3.86%,48.30% ± 4.16% and 81.80% ± 6.72%,with a significant difference(P < 0.05).Cells treated with oridonin showed typical apoptotic features with acridine orange/ethidium bromide staining.After treatment with oridonin,the cells became round,shrank,and developed small buds around the nuclear membrane while forming apoptotic bodies.Lactate dehydrogenase(LDH) release assay showed that after treated with 1.25 μg/mL and 20 μg/mL oridonin for 24 h,LDH release of HGC-27 caused by apoptosis increased from 22.94% ± 3.8% to 52.68% ± 2.4%(P < 0.001).However,the change in the release of LDH caused by necrosis was insignificant,suggesting thatthe major cause of oridonin-induced HGC-27 cell death was apoptosis.Flow cytometric analysis also revealed that oridonin induced significant apoptosis compared with the controls(P < 0.05).And the apoptosis rates of HGC-27 induced by the four different concentrations of oridonin were 5.3% ± 1.02%,12.8% ± 2.53%,28.5% ± 4.23% and 49.6% ± 3.76%,which were in a dose-dependent manner(P < 0.05).After treatment for 24 h,DNA ladder showed that oridonin induced a significant increase in DNA fragmentation in a dosedependent manner.RT-PCR revealed that mRNA expression levels were up-regulated compared with the controls in caspase-3(0.917 ± 0.103 vs 0.357 ± 0.019,P < 0.05),cytochrome c(1.429 ± 0.111 vs 1.002 ± 0.014,P < 0.05),Apaf-1(0.688 ± 0.101 vs 0.242 ± 0.037,P < 0.05) and Bax(0.856 ± 0.101 vs 0.278 ± 0.027,P < 0.05)(P < 0.05),whereas down-regulated in Bcl-2(0.085 ± 0.012 vs 0.175 ± 0.030,P < 0.05).Western blotting analysis also confirmed this result.CONCLUSION:Apoptosis of HGC-27 induced by oridonin may be associated with differential expression of Apaf-1,caspase-3 and cytochrome c,which are highly dependent upon the mitochondrial pathway.
基金the grant form the Guangdong Science and Technology De-partment (No. 2006B35630009).
文摘OBJECTIVE To study the inhibitory effect of oridonin on the growth of cancer cells. METHODS Fifteen human cancer cell lines were subjected to various concentrations of oridonin in culture medium. The inhibitory rate of cell growth was measured by the MTT assay, and compared with a negative con- trol and 5-Fu-positive control. RESULTS The 50% inhibiting concentration (IC50) and maximal inhibition (Imax) of oridonin shown by studying the growth of the cancer cell lines were as follows: leukemias (HL60 cells: 3.9 μg/ml and 73.8%, K562 cells: 4.3 μg/ml and 76.2%); esophageal cancers(SHEEC cells: 15.4 μg/ml and 99.2%, Eca109 cells: 15.1 μg/ml and 84.6%, TE1 cells: 4.0 μg/ml and 70.2%); gastric cancers (BGC823 cells: 7.6 μg/ml and 98.7%, SGC7901 cells: 12.3 μg/ml and 85.7%); colon cancers (HT29 cells: 13.6 μg/ml and 97.2%, HCT cells: 14.5 μg/ml and 96.5%); liver cancers (Bel7402 cells: 15.2 μg/ml and 89.2%, HepG2 cells: 7.1 μg/ml and 88.3%); pancreatic cancer (PC3 cells: 11.3 μg/ml and 68.4%); lung cancer (A549 cells: 18.6 μg/ml and 98.0% ); breast cancer (MCF7 cells: 18.4 μg/ml and 84.7%); uterine cervix cancer (Hela cells: 13.7 μg/ml and 98.5%). CONCLUSION Oridonin had a relatively wide anti-tumor spectrum, and a relatively strong inhibitory effect on the growth of the 15 human cancer cells. Inhibitory effects were concentration dependent.
文摘ObjectiveTo investigate the anti-proliferation effect of oridonin on leukemic HL-60 cells and its mechanism. Methods HL-60 cells invitroin culture medium were given different concentrations of oridonin. The inhibitory rate of cells were measured by microculture tetrazolium (MTT) assay, cell apoptotic rate was detected by flow cytometry (FCM),morphology of cell apoptosis was observed by hoechst 33258 fluorescence staining, and the activity of telomerase was det-ected using telomere repeat amplification protocol (TRAP) PCR-ELISA before and after apoptosis occurred. Results Oridonin could decrease telomerase activity, inhibit growth of HL-60 cells, and cause apoptosis significantly. The suppression was both in time- and dose-dependent manner. Marked morphological changes of cell apoptosis including condensation of chromatin and nuclear fragmentation were observed clearly by hoechst 33258 fluorescence staining especi-ally after cells were treated 48-60 hours by oridonin. Conclusions Oridonin has apparent anti-proliferation and apoptotic effects on HL-60 cells invitro, decreasing telomerase activity of HL-60 cells may be one of its most important mechanisms. These results will provide strong laboratory evidence of oridonin for clinical treatment of acute leukemia.
文摘Objective: To investigate the effect of oridonin on proliferation and invasion of human multiple myeloma LP-1 cells and the underlying mechanism. Methods: LP-1 cells in culture medium in vitro were treated with oridonin at the different concentration. Cell proliferation was measured by Microwave Theory and Techniques (MTT) assay and cell apoptotic rate was detected by flow cytometry. Morphology of cell apoptosis was observed by transmission electron microscope. Expressions of Bax, Bcl-2, Caspase-3, NF-κB as well as I-κB mRNA were detected by real-time PCR. Results: The MTT assays and flow cytometry revealed that oridonin could inhibit the growth of LP-1 cells and cause apoptosis significantly; the suppression was both in time- and dose-dependent manner. Marked morphological changes of cell apoptosis were found under a transmission electron microscope after the cells were treated with oridonin at 25 μmol/L for 24 h. Along with the apoptotic process, Bcl-2, Caspase-3,NF-κB gene expressions were down-regulated (P<0.05). On the contrast, the Bax and I-κB gene expressions were up-regulated (P<0.05). Conclusion: Oridonin could inhibit the proliferation of LP-1 cells via inducing apoptosis. We concluded that oridonin induces apoptosis in LP-1 cells via activation of caspase-3 as well as down-regulation of Bcl-2 and up-regulation of Bax expression. The results suggested that oridonin could induce apoptosis of LP-1 cells through mitochondria- and caspase3-dependent pathways. Meanwhile, the inhibition of NF-κB and the activation of I-κB indicate pro-apoptotic stimuli. In one word, oridonin might be an important potential anti-myeloma reagent.
基金funded by the National Key R&D Program of China(2018YFA0900600)the National Natural Science Foundation of China(32070328,22077129,and 41876084),the Program of Shanghai Academic Research Leader(20XD1404400)+2 种基金the Strategic Priority Research Program“Molecular Mechanism of Plant Growth and Development”of CAS(XDB27020202)the Construction of the Registry and Database of Bioparts for Synthetic Biology of the Chinese Academy of Sciences(ZSYS-016),the International Partnership Program of the Chinese Academy of Sciences(153D31KYSB20170121),Derivative Bank of Chinese Biological Resources(KFJ-BRP-009-002)the National Key Laboratory of Plant Molecular Genetics,SIPPE,CAS.Y.S.is supported by the Foundation of Youth Innovation Promotion Association of the Chinese Academy of Sciences.
文摘The ent-kaurenoids(e.g.,oridonin and enmein)from the Isodon genus(Lamiaceae)are one class of diterpenoids with rich structural diversity and intriguing pharmaceutical activity.In contrast to the well-established gibberellin pathway,oxidative modifications diversifying the ent-kaurene skeleton in Isodon have remained undetermined for half a century.Here we report a chromosome-level genome assembly of I.rubescens,a well-recognized oridonin producer long favored by Asian people as a traditional herb with antitumor effects.The shoot apex was confirmed to be the actual region actively producing ent-kaurene diterpenoids.Through comparative genomics and phylogenetic analyses,we discovered a cluster of tandem-duplicated CYP706V oxygenase-encoding genes located on an ancient genomic block widely distributed in eudicots,whereas almost exclusively emerged in Isodon plants.In the shoot apex,IrCYP706V2 and IrCYP706V7 oxidized the ent-kaurene core in the initial stage of oridonin biosynthesis.Loss of CYP706Vs in other Lamiaceae plants offered an explanation for the specific kaurenoid production in Isodon plants.Moreover,we found that the Isodon genomes encode multiple diterpenoid synthases that are potentially involved in generating diterpenoid diversity.These findings provided new insights into the evolution of the lineage-specific diterpenoid pathway and laid a foundation for improving production of bioactive ent-kaurene-type diterpenoids by molecular breeding and synthetic biology approaches.
基金the Creative Research Group Program of Natural Science Foundation of Hubei Province(2022CFA021)the China Postdoctoral Science Foundation(2022M720895)+1 种基金the National Natural Science Foundation of China(3210011 and 32200132)the Natural Science Foundation of Hubei Province,China(2017CFB535).
文摘COVID-19 has become a global public health crisis since its outbreak in China in December 2019.Currently there are few clinically effective drugs to combat SARS-CoV-2 infection.The main protein(M^(pro)),papain-like protease(PL^(pro))and RNA-dependent RNA polymerase(RdRp)of SARS-CoV-2 are involved in the viral replication,and might be prospective targets for anti-coronavirus drug development.Here,we investigated the antiviral activity of oridonin,a natural small-molecule compound,against SARS-CoV-2 infection in vitro.The time-of-addition analysis showed that oridonin efficiently inhibited SARS-CoV-2 infection by interfering with the genome replication at the post-entry stage.Mechanistically,the inhibition of viral replication by oridonin depends on the oxidation activity ofα,β-unsaturated carbonyl.Further experiments showed that oridonin not only effectively inhibited SARS-CoV-2 Mpro activity,but also had some inhibitory effects on PLpro-mediated deubiquitinating and viral polymerase-catalyzed RNA elongation activities at high concentrations.In particular,oridonin could inhibit the bat SARS-like CoV and the newly emerged SARS-CoV-2 omicron variants(BA.1 and BA.2),which highlights its potential as a pan-coronavirus antiviral agent.Overall,our data provide strong evidence that oridonin is an efficient antiviral agent against SARS-CoV-2 infection.
基金supported in part by grants from the National Key Technologies R&D Program for New Drugs of China (No. 2012ZX09301003-001-009)the Beijing Natural Science Foundation of China (No.7154230)
文摘Non-small cell lung cancer(NSCLC) accounts for about 85% of all lung cancers. Traditional chemotherapy for this disease leads to serious side effects. Here we prepared an inhalable oridonin-loaded poly(lactic-co-glycolic)acid(PLGA) large porous microparticle(LPMP) for in situ treatment of NSCLC with the emulsion/solvent evaporation/freeze-drying method. The LPMPs were smooth spheres with many internal pores. Despite a geometric diameter of 10 mm, the aerodynamic diameter of the spheres was only 2.72 mm, leading to highly efficient lung deposition. In vitro studies showed that most of oridonin was released after 1 h, whereas the alveolar macrophage uptake of LPMPs occurred after 8 h, so that most of oridonin would enter the surroundings without undergoing phagocytosis. Rat primary NSCLC models were built and administered with saline, oridonin powder, gemcitabine, and oridonin-loaded LPMPs via airway, respectively. The LPMPs showed strong anticancer effects. Oridonin showed strong angiogenesis inhibition and apoptosis. Relevant mechanisms are thought to include oridonin-induced mitochondrial dysfunction accompanied by low mitochondrial membrane potentials, downregulation of BCL-2 expressions, upregulation of expressions of BAX, caspase-3 and caspase-9. The oridonin-loaded PLGALPMPs showed high anti-NSCLC effects after pulmonary delivery. In conclusion, LPMPs are promising dry powder inhalations for in situ treatment of lung cancer.
文摘Collaboration of c-KIT mutations with AML1-ETO (AE) has been demonstrated to induce t(8;21) acute myeloid leukemia (AML).Targeted therapies designed to eliminate AE and c-KIT oncoproteins may facilitate effective treatment of t(8;21) AML.Homoharringtonine (HHT) features activity against tumor cells harboring c-KIT mutations,whereas oridonin can induce t(8;21) AML cell apoptosis and AE cleavage.Therefore,studies should explore the efficacy of combination therapy with oridonin and HHT in t(8;21) AML.In this study,we investigated the synergistic effects and mechanism of oridonin combined with HHT in t(8;21) AML cell line and mouse model.The two drugs synergistically inhibited cell viability and induced significant mitochondrial membrane potential loss and apoptosis.Oridonin and HHT induced significant downregulation of c-KIT and its downstream signaling pathways and promoted AE cleavage.HHT increased intracellular oridonin concentration by modulating the expressions of MRP1 and MDR1,thus enhancing the effects of oridonin.The combination of oridonin and HHT prolonged t(8;21) leukemia mouse survival.In conclusion,oridonin and HHT exert synergistic effects against t(8;21) leukemia in vivo and in vitro,thereby indicating that their combination may be an effective therapy for t(8;21) leukemia.
基金Q.Shen and J.Zhou were supported in part by the National Institutes of Health(NIH)/National Cancer Institute(NCI)grants(grant numbers R01CA231150,R01CA226001)。
文摘Cancer is one of the diseases with high morbidity and mortality on a global scale.Chemotherapy remains the primary treatment option for most cancer patients,including patients with progressive,metastatic,and recurrent diseases.To date,hundreds of chemotherapy drugs are used to treat various cancers,however,the anti-cancer eficacy and outcomes are largely hampered by chemotherapy-associated toxicity and acquired therapeutic resistance.The natural product(NP)oridonin has been extensively studied for its anti-cancer efficacy.More recently,oridonin has been shown to overcome drug resistance through multiple mechanisms,with yet-to-be-defined bona fide targets.Hundreds of oridonin derivative analogs(oridonalogs)have been synthesized and screened for improved potency,bioavailability,and other drug properties.Particularly,many of these oridonalogs have been tested against oridonin for tumor growth inhibition,potential for overcoming therapeutic resistance,and immunity modulation.This concise review seeks to summarize the advances in this field in light of identifying clinical-trial level drug candidates with the promise for treating progressive cancers and reversing chemoresistance.
基金supported by the Science and Technology Development Fund of the Macao Special Administrative Region(Nos:071/2009/A3 and 091/2009/A).
文摘Oridonin,a diterpenoid isolated from Rabdosia rubescens(Hemsl.)Hara,has been proved to possess remarkable anticancer activity,in addition to its potential in antiinflammation and antibacteria.The purpose of this article is to review current progress in oridonin concerned about a relationship between the chemical structure/modifications and its anticancer activity and to discuss the molecular mechanisms underlying its anticancer activity,such as suppression of tumor proliferation and induction of tumor cell death,and the cell signal transduction in anticancer activity of oridonin.
