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@#Eubhorbia neriifolia L. is a plant of Euphorbia family.Five known lignans were isolated from the aerial parts of E. neriifolia L. by silica gel for column chromatography and preparative high-performance liquid chromatography (HPLC).Their potential antitumor activities were evaluated in vitro.Compound 2 exhibited proliferation inhibition and cytotoxicity against esophageal squamous cancer cells, especially KYSE-410 and KYSE-450 cells.Further analyses showed that compound 2 could significantly induce apoptosis through the activation of caspase 3/9 and down-regulation of the Bcl-2/Bax protein ratio.These results suggested that compound 2 had a significant inhibitory effect on the esophageal squamous cancer cells, especially KYSE-410, which deserves further research as a potential antitumor agent.
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Integrins are transmembrane receptors that have been implicated in the biology of various human physiological and pathological processes. These molecules facilitate cell-extracellular matrix and cell-cell interactions, and they have been implicated in fibrosis, inflammation, thrombosis, and tumor metastasis. The role of integrins in tumor progression makes them promising targets for cancer treatment, and certain integrin antagonists, such as antibodies and synthetic peptides, have been effectively utilized in the clinic for cancer therapy. Here, we discuss the evidence and knowledge on the contribution of integrins to cancer biology. Furthermore, we summarize the clinical attempts targeting this family in anti-cancer therapy development.
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MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA-c), a mitochondrial-derived 16-amino acid peptide, targets the methionine-folate cycle, increases 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) levels, and eventually activates AMP-activated protein kinase (AMPK). AMPK activation can attenuate neutrophil pro-inflammatory activity and attenuates lipoteichoic acid (LTA) and lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice. However, to our knowledge, the role of MOTS-c in LPS-induced ALI remains unclear. Hence, we investigated the potential effectiveness and underlying mechanism of MOTS-c against LPS-induced ALI in mice. The intraperitoneal administration of MOTS-c (5 mg/kg, i.p., bid, 6 days) before intratracheal LPS instillation attenuated body weight loss and pulmonary edema, inhibited neutrophilic tissue infiltration in lung tissue, downregulated the expression of cytokine-induced neutrophil chemoattractant-1 (CINC-1) and intercellular cell adhesion molecule-1 (ICAM-1) in lung tissues, decreased the levels of TNF-α, IL-1ß, and IL-6, and increased the expression of IL-10 and SOD in serum, lung tissue, and bronchoalvelolar lavage fluid (BALF). Moreover, MOTS-c treatment significantly promoted p-AMPKα and SIRT1 expression and suppressed LPS-induced ERK, JNK, p38, p65, and STAT3 activation in the mouse lung tissues. Collectively, these findings suggest that MOTS-c plays important roles in protecting the lungs from the inflammatory effects of LPS-induced ALI. The effects of MOTS-c are probably orchestrated by activating AMPK and SIRT1, inhibiting ERK, JNK, p65, and STAT3 signaling pathways. Thus, MOTS-c appears to be a novel and promising candidate for the treatment of ALI.
Subject(s)
Acute Lung Injury/drug therapy , Anti-Inflammatory Agents/therapeutic use , Mitochondrial Proteins/therapeutic use , Acute Lung Injury/chemically induced , Acute Lung Injury/immunology , Acute Lung Injury/pathology , Animals , Cytokines/immunology , Lipopolysaccharides , Lung/drug effects , Lung/immunology , Lung/pathology , Male , Mice , Mice, Inbred BALB CABSTRACT
To develop fusion protein of a GnRH Fc fragment and the integrin targeting AP25 antitumor peptide for GnRH receptor-expressing cancer therapy. The LMRAP fusion protein was constructed. A transwell invasion assay was performed. The gene mRNA and protein levels of GnRHR-I, 51, and v3 in different cancer cell lines were assessed. Cell proliferation was measured using a cell counting kit-8. An antagonist assay was performed on GnRH receptors. Anti-tumor activity was evaluated with a mouse xenograft tumor model. Immunohistochemistry (IHC) was applied to detect CD31 and CD34 expressions. Pharmacokinetic characteristics were determined with an indirect competition ELISA. The developed bifunctional fusion protein LMRAP not only inhibited HUVEC invasion, but also inhibited proliferation of GnRHR-I, 51, and v3 high expression cancer cells. The IC for LMRAP in the GnRH receptor was 6.235 × 10 mol/L. LMRAP significantly inhibited human prostate cancer cell line 22RV1 proliferation and . LMRAP significantly inhibited CD31 and CD34 expressions. The elimination half-life of the fusion protein LMRAP was 33 h in rats. The fusion protein made of a GnRH Fc fragment and the integrin targeting AP25 peptide retained the bifunctional biological activity of GnRHR blocking, angiogenesis inhibition, prolonged half-life and good tolerance.
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Aim To study the anti-inflammatory activity of the Channa argus bile.Methods The bile was isolated and purified by extraction and silica gel column chromatography.Then the compounds were identified by hydrogen and carbon spectra.The spleen lymphocytes proliferation assay and Lipopolysaccharide(LPS) induced mouse macrophage RAW264.7 releasing Nitrogen Monoxide(NO) experiment were used to evaluate the anti-inflammatory activity.Results Compound(C1) of sodium taurocholate and compound(C2) of sodium taurochenodeoxycholate were isolated by activity tracing.The cell relative viabilities of the two compounds on Concanavalin A(Con A) induced spleen lymphocytes proliferation assay were 65.9%±11.7% and 60.5%±9.4%, which were significantly different from the result of model group (P<0.01), respectively.The NO production of LPS-induced RAW264.7 release of NO was (16.4±1.9) μmol·L-1 and (15.5±1.7) μmol·L-1, which were significantly different from the result of model group(P<0.01).Conclusion Sodium taurocholate and sodium taurochenodeoxycholate from Channa argus perform the anti-inflammatory activities but have no cytotoxic effect on spleen lymphocytes and macrophage.
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Aims Toevaluatethepharmacodynamic efficacy of different types of antiangiogenic agents as HM-3 on a non-small cell lung cancer xenografts tumor model .To explore the interaction between the antian-giogenic agents and the tumor microenvironment,and to offer suggestions for clinical therapy.Methods Thenon-smallcelllungcarcinomaxenograftmodelwas established in Balb/c nude mice.The model mice were treated with Docetaxel(10 mg·kg-1 )as the positive control.The mice were parallelly treated with,HM-3 at the doses of 3 mg · kg-1 and 48 mg · kg-1 and, Avastin(5 mg·kg-1 ).The parameters include tumor volume,tumor weight and immunohistochemical analy-sis.Result Animalexperimentsshowedthatdocetaxel had good anti-tumor activity.Tumor growth inhibition by tumor weight of G2 docetaxel(10 mg·kg-1 )group was 60. 80%.Tumor growth inhibition by tumor weight of G3 HM-3(3 mg·kg-1 )group,G4 HM-3(48 mg· kg-1 )group ,G4 Avastin(5 mg·kg-1 )group,were 43. 60%,-34. 80%,44. 40%,respectively.Con-clusion Theantigiogeniceffectisaffectedbytumor growth stage,tumor microenvironment and their work-ing mechanisms.Angiogenesis inhibitors HM-3 has a certain effect of inhibiting tumor growth,but to little a-vail.HM-3 shows on inhibitory effect in a dose-de-pendent manner at the doses of 0~6 mg·kg-1 .HM-3 at a high dose of 48 mg · kg-1 has no inhibitory but promoting effects on human non-small cell lung carci-noma A549 xenografts in nude mice .Special dose-effect relationship indicates that dosage should be paid attention to in the clinical use of blood vessel inhibi-tors.
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@#mPEG-SC20k-HM-3 is a novel anti-angiogenesis peptide with integrin affinity. To investigate the anti-tumor activities of mPEG-SC20k-HM-3 and oxaliplatin(OXA)combination, a transplanted tumor model of human hepatocellular carcinoma SMMC-7721 in nude mice was established. Jin′s formula to evaluate the combination effect was used. Data suggested that the anti-tumor activities of combined groups were better than those of single drug(P< 0. 05). Inhibition rate of group 8(OXA 7. 5 mg/kg and mPEG-SC20k-HM-3 73. 4 mg/kg)was 84. 6%, which showed remarkable superiority to group 3(OXA 7. 5 mg/kg)and group 4(mPEG-SC20k-HM-3 73. 4 mg/kg). The Q of group 8 was 1. 164(> 1. 15). This combination had synergistic effect. Combination of mPEG-SC20k-HM-3 and oxaliplatin is a method of inhibiting hepatocellular carcinoma.
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Aim To evaluate whether the combination of polypeptide AP25 and docetaxel is more efficient in treating experimental breast cancer,than either reagent used alone,and to offer suggestions for clinical use. Methods An experimental breast carcinoma model was set up to investigate the anti-tumor effects of AP25 and docetaxel combination.The Q value was caluculat-ed by Guinness rules and the anti-tumor effects of the combination of polypeptide AP25 and docetaxel were e-valuated.Results The treatment by the combination of polypeptide AP25 and docetaxel showed a better tumor inhibition rate.The combination of AP25 20 mg ·kg -1 and docetaxel 10 mg·kg -1 significantly inhibi-ted the tumor growth with 0.85 1.15,showing a synergistic effect.Conclusions The combination of AP25 and docetaxel can significantly in-hibit the tumor growth with a synergistic effect and de-crease the dose of chemotherapy.
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PEGylation improves the pharmacokinetic and pharmacodynamic properties of polypeptide drugs. After PEGylation, the modified HM-3 (PEG-HM-3) exhibited a prolonged half-life in blood. In this paper, we evaluated the anti-rheumatic effect of PEG-HM-3, and investigated the target for angiogenesis and inflammation. The anti-rheumatic activity of PEG-HM-3 was documented in an adjuvant-induced arthritis (AIA) model. PEG-HM-3 significantly decreased the paw increase percentage and clinical scores, inhibited characteristic signs such as synovial hyperplasia, pannus formation, inflammatory infiltration and bone erosion in histological analysis, and reduced bone erosion with the X-ray analysis of the hint paws of rats. The target for angiogenesis and inflammation was assessed with in vivo and in vitro techniques. The in vivo experiments confirmed that PEG-HM-3 decreased the number of blood vessels in rheumatic synovium, reduced the level of serum anti-CII autoantibodies, and decreased the levels of synovial TNF-alpha and VEGF in a collagen-induced arthritis (CIA) model. The in vitro results confirmed that the anti-angiogenic effect of PEG-HM-3 was mainly achieved through the inhibition of HUVEC migration. PEG-HM-3 inhibited the mitotic effects in the T-cell population. PEG-HM-3 could significantly inhibit the TNF-alpha and VEGF levels in the LPS-stimulated macrophage and the latter effect was stronger than that seen with HM-3. Furthermore, the simulated molecule docking result showed that the RGD motif of PEG-HM-3 inserted into the pocket site of integrin αvß3, and PEG-HM-3 had a higher predicted affinity with integrin αvß3 compared to the predicted affinity of HM-3 and integrin αvß3. This study has uncovered that PEGylate HM-3 could present an anti-rheumatic bioactivity with a less frequent schedule, and PEG-HM-3 exhibited its anti-rheumatic effects by inhibiting angiogenesis and inflammation. Furthermore, the main targeting site has been confirmed, which explained the changes in the bioactivity of PEG-HM-3.
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Aim To investigate the expression of CD31 , CD105 , HIF-1αand VEGF in xenografts tumor of HT-29 tumor cells during different stages of growth. Methods HT-29 tumor cells were transplanted into nude mice, the tumor was removed when the tumor volumes reached 300 mm3 respectively. Immunochemical method was a-dopted to detect the expression of CD31 , CD105 , HIF-1α and VEGF. Results HT-29 xenografts tumor vol-umes 300 mm3 showed expressions with CD31-MVD at 37.40±4.17 , 18.80±1.72 and 14.20±2.23 respectively; CD105-MVD at 22.80 ±3.54 , 15.60 ±1.35 and 10.20 ±2.48; positive expression rate of VEGF was 26.20% ±0.83%,40.73% ±6.29% and 13.41% ±1.20%respectively; while positive expression rate of HIF-1αwas 3.20% ± 2.97%, 11.89% ± 1.94% and 80.62% ±3.47% respectively. On the other hand, for different volumes group, CD31-MVD, CD105-MVD, VEGF and HIF-1αexpression ratios had signifi-cant differences ( P <0.01 ) . Conclusions The ex-pression of MVD and vascular-related factors within the tumor caused by HT-29 xenografts tumor in nude mice at different growth stages was varied. There was a cer-tain correlation between tumor volume and MVD, VEGF, HIF-1α.
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The generation and activity of serum neuralizing antibody in cynomolgus monkeys and SD rats undergoing long-term toxicity study with antitumor peptides HM-3 were investigated.The rats were administered intravenously with HM-3 at doses of 4.5 mg/kg,13.5 mg/kg,and 40.5 mg/kg for 6 months,and the cynomolgus monkeys were administrated intravenously with HM-3 at doses of 3 mg/kg,9 mg/kg and 27 mg/kg for 6 months,respectively.Anti-HM-3 antibodies and their neutralizing activities in serum samples taken every month after the administrations were determined by ELISA and cell migration assay,respectively.During the long-term administrations,anti-HM-3 antibodies were generated in some SD rats at high and moderate dose groups,and the antibody-neutralizing activities could be detected in a number of these samples (P ＜0.05).However,activity could be detected in very few monkeys (P ＜ 0.05),and the antibody titers were not correlated with the neutralizing activities.Therefore,we conclude that the antigenicity of HM-3 was low,but after long-term administration at high dose,low affinity neutralizing antibody could be generated in small number of samples.
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With the development of the research on biotechnology and modern pharmacy, the application of enzyme drugs have grown rapidly and enzyme drugs have become an important branch of biopharmaceutics. In this article, some new varieties of therapeutic enzymes, enzyme targets, mechanisms and new technologies of application in therapeutic enzymes were reviewed, and the direction of development of therapeutic enzymes were discussed.
Subject(s)
Adenosine Deaminase , Genetics , Therapeutic Uses , Antineoplastic Agents , Therapeutic Uses , Enzyme Replacement Therapy , Methods , Fibrinolytic Agents , Therapeutic Uses , Protein C , Genetics , Therapeutic Uses , RNA, Catalytic , Genetics , Therapeutic Uses , Streptokinase , Genetics , Therapeutic Uses , Urokinase-Type Plasminogen Activator , Genetics , Therapeutic UsesABSTRACT
Aim To investigate effects of ZX-5 on the expression and activity of nitric oxide synthase ( NOS) in endothelial cells,and to confirm which kind of NOS increases NO production and promote choroidal blood flow in ZX-5 -induced HUVECs. Methods HUVECs ( human umbilical vein endothelial cells) were used to determine the expression of eNOS,iNOS and nNOS by Western blot; the activities of NOS were investigated by the corresponding kit. Results ( R,R) ZX-5 upregulated eNOS expression and increased NO production; ( S,S) ZX-5 upregulated iNOS expression and slightly increased NO release. Conclusions ( R,R) ZX-5 promotes choroidal blood flow via upregulating eNOS expression and activity and promoting NO production; the compound may be used for the prevention and treatment of age-related macular degeneration in the elderly.
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With the development of recombinant DNA technology, genetically altered mouse models for human cancers are critical to the investigation and characterization of oncogene and tumor suppressor gene expression and function and the associated cancer phenotype. Recently, the inhibition of tumor angiogenesis becomes a new “hot spot” in cancer researches. And the genes involved in the regulation of tumor angiogenesis play an increasingly important role in the field of tumor researches. This review is about the progress of the research in transgenic tumor models and focuses on genes regulating tumor angiogenesis associated with transgenic mice model.
