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Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.
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OBJECTIVE： To investigate the effects of benzoxazole derivative 2-（chlorobenzoxazolyl-2-yl）-4，5，6，7-tetrahydro- dihydro-indazole-3-ol （PO-296） on the differentiation of murine bone marrow-derived dendritic cells（DC） and their related indexes as specific surface molecules and inflammatory cytokines. METHODS： Bone marrow nuclear cells of mice were isolated， and immature DC （imDC） was obtained by recombinant mice granulocyte macrophage colony-stimulating factor and recombinant mice IL-4. After pretreated with low-dose， medium-dose and high-dose （1， 5， 25 μmol/L） of PO-296， DC was obtained by lipopolysaccharide induction. Flow cytometry was used to detect the expression of DC specific surface molecules [i.e. the proportion of class Ⅱ major histocompatibility complex （MHC Ⅱ）， CD80， CD86 and chemokine receptor 7 （CCR7） positive cells]， imDC phagocytosis （i.e. the proportion of dextran positive cells） and DC survival （i.e. the proportion of survival cells）. ELISA method was used to detect the levels of inflammatory cytokines （IL-10， IL-12 and TNF-α） in cell culture medium. RESULTS： Compared with imDC group， the proportion of MHC Ⅱ， CD80 and CD86 positive cells were increased significantly in non-loading group （P＜0.05）. Compared with non-loading group， the levels of IL-10 in cell culture medium were increased significantly in PO-296 groups. The proportions of MHC Ⅱ， CD80 and CD86 positive cells in positive group and PO-296 medium-dose and high-dose groups as well as the levels of IL-12 and TNF-α in cell culture medium in administration groups were decreased significantly （P＜0.05）. There was no statistical significance in the proportion of CCR7 positive cells， dextran positive cells and survival cells in administration groups， compared with non-loading group （P＞0.05）. CONCLUSIONS： PO-296 has no obvious cytotoxicity and does not affect the phagocytic function of imDC. At the same time， the compound can inhibit the expression of DC specific surface molecules and regulate the secretion of inflammatory cytokines.
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Objective To investigate the effect of long-term proton pump inhibitor on osteoporosis in elderly patients.Methods A total of 150 patients with peptic ulcer treated in our hospital from January 2011 to January 2015 were selected as the observation group.150 healthy subjects were selected as the control group.The age,height,body weight and PPI time of the two groups were recorded.The changes of bone mineral density before and after treatment were measured by bone mineral density analyzer,ineluding lumbar L1-4,radial density and ulna density.The changes of bone mineral density were observed and recorded in the observation group before treatment,six months,1 year and 2 years after treatment.Results After treatment,the levels of gastrin were significantly increased in the observation group,and the serum calcium concentration and bone mineral density were significantly decreased (P＜0.05).The density of lumbar vertebrae,radius and ulna was significantly lower in observation group than those of control group (P＜0.05).With the prolongation of PPIs,lumbar vertebrae,radius and ulna density in observation group showed a decreasing trend.Conclusion Long-term application of proton pump inhibitors in elderly patients can cause bone loss.
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Objective To investigate the correlation between the drug resistance of Helicobacter pylori (H .pylori )and clinical eradication efficacy of bismuth-based quadruple therapies,and to guide clinical rational drug use in the region.Methods A total of 260 patients with H .pylori infections were collected.H .pylori from biopsied gastric mucosa tissues were isolated and cultured.Drug resistant rates of isolated H .pylori to metronidazole,clarithromycin,amoxicillin,levofloxacin and furanzolidone were tested.Patients were randomly divided into clarithromycin,levofloxacin,furanzolidone and metronidazole groups by completely randomized design.All patients received bismuth potassium 220 mg,esomeprazole 20 mg and amoxicillin 1 000 mg twice daily,and according to group received clarithromycin 500 mg, levofloxacin 200 mg,furanzolidone 100 mg and metronidazole 400 mg,twice daily,espectively.The treatment course was 10 days.At least four weeks after treatment,13 Curea breath test or 14 Curea breath test was taken.According to the intention to treat (ITT)and per-protocal (PP),the eradication rate of each group was caculated.Chi square test was performed to compare the differences between groups. Results The drug resistant rate of H .pylori to metronidazole,clarithromycin,amoxicillin,levofloxacin and furanzolidone was 94.2% (146/155 ), 21 .3% (33/155 ), 2.6% (4/155 ), 5 .8% (9/155 ) and 1 .9%(3/155),respectively.According to ITT analysis,the eradication rate of clarithromycin group, levofloxacin group,furanzolidone group and metronidazole group was 81 .5 %(53/65 ),90.8%(59/65 ), 93.8% (61/65 )and 75 .4%(49/65),respectively.And according to PP analysis which was 84.1 %(53/63),92.2%(59/64),95 .3%(61/64)and 79.0%(49/62 ),respectively.The differences between furanzolidone group and metronidazole group,clarithromycin group were staistcally significant (χ2ITT =8.509 and 4.561 ;χ2PP = 7.592 and 4.323,all P < 0.05 ).There was no statistical significance in the H .pylori eradication rate between resistant strains and sensitive strains of each group.Conclusion Bismuth-based quadruple therapy can overcome antibiotic resistance,the eradication rate of protocal with furanzolidone is higher and with good safety,which can be the first-line treatment for H .pylori eradication.
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Objective To study the effect of gauzes with composite lysozyme on chemotherapeutic phlebitis. Methods One hundred and twenty patients with chemotherapeutic phlebitis were equally randomized into the experiment group and control group with radom digit tade. The experiment group was treated by hydropathic compress with gauzes with composite lysozyme on the affected parts, while the control group was treated by hydropathci compress with 50%magnesium sulfate solution. The therapeutic effects after 1 week were compared between the two groups . Results The effective rate of the experiment group was significantly higher than that of the control group (P < 0.05). The average time for the treatment was significantly shorter than the control group (P < 0.05). Conclusion The effect of composite lysozyme for hydropathic compress in the treatment of chemotherapeutic phlebitis is better than that of 50%magnesium sulfate. It is worthy of clinical popularization and application.
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Objective To evaluate the efficacy and safety of different bismuth-based quadruple therapies for Helicobacter pylori (H.pylori) eradication.Methods From December 2012 to October 2013,240 patients with H.pylori infection were collected and evenly divided into clarithromycin group,levofloxacin group,furanzolidone group and metronidazole group.Each group received bismuth potassium citrate 220 mg,esomeprazole 20 mg and amoxicillin 1 000 mg twice daily.In addition,each group received clarithromycin 500 mg,levofloxacin 200 mg,furanzolidone 100 mg,and metronidazole 400 mg,respectively.The course of treatment was 10 days.At least four weeks after the end of therapy and withdrawal the medicine,patients underwent fasting 13C-urea breath test or 14C-urea breath test.The negative result indicated as successful H.pylori eradication.The adverse effects were observed and recorded during treatment.The rate of H.pylori eradication was analyzed by the intention to treat (ITT) analysis and per protocol (PP) analysis.Chi-square test was performed for eradication rate comparison among groups.Results According to ITT analysis,the eradication rate of clarithromycin group,levofloxacin group,furanzolidone group and metronidazole group was 81.67％ (49/60),88.33％ (53/60),93.33％ (56/60) and 73.33％ (44/60),respectively,and according to PP analysis which was 85.96％ (49/57),89.83％ (53/59),94.92％ (56/59) and 75.86％ (44/58),respectively.The differences among four groups were statistically significant (x2 ＝10.13 and 9.89,both P＜0.05).The differences between furanzolidone group and metronidazole group were statistically significant (x2 =8.64 and 8.55,both P＜0.01).There were no statisticaly significant differences in adverse effects among the four groups (x2 =0.47,P＞0.05).Conclusion The H.pylori eradication rate is high in furanzolidone contained bismuth based quadruple therapy and with good safety,which could be the first line treatment for H.pylori eradication.