替加环素与5种抗生素对多重耐药鲍曼不动杆菌体外联合药敏实验的研究

分析亚胺培南、头孢哌酮-舒巴坦、头孢曲松、左氧氟沙星、庆大霉素5种临床常用鲍曼不动杆菌治疗的抗生素单用和分别与替加环素联用的体外敏感性实验的研究,以期发现较好的联合用药方案,为临床合理使用抗生素提供用药参考。采用微量肉汤稀释法测定5种抗生素对鲍曼不动杆菌的MIC值,再采用棋盘法测定5种抗生素分别与替加环素联用MIC值,并计算FIC指数。结果显示,替加环素与亚胺培南、头孢哌酮舒巴坦、左氧氟沙星、头孢曲松具有协同和相加作用,替加环素与庆大霉素具有拮抗作用。临床在选择抗生素治疗鲍曼不动杆菌所引起的重症感染时,可根据该药敏实验结果与亚胺培南或头孢哌酮舒巴坦或左氧氟沙星或头孢曲松与替加环素联合使用,但应避免与庆大霉素联合使用。     

替加环素与米诺环素治疗布鲁菌病的进展

布鲁菌病是由布鲁菌引起的人畜共患传染性疾病，由带菌动物通过多种途径传染给易感人群，可侵犯人体各器官系统。目前推荐的抗布鲁菌治疗方案为多西环素、利福平、喹诺酮类、氨基糖类等抗菌药物组合的二联或者三联抗菌方案，但治疗无效率和疾病复发率仍较高。替加环素和米诺环素作为四环素类药物，经体外实验证明均可有效抑制布鲁菌，且50%最小抑菌浓度（50% minimal inhibitory concentration，MIC50） 和 90%最小抑菌浓度（90% minimal inhibitory concentration，MIC90）均较低。临床研究亦证实，包含替加环素和米诺环素的联合抗菌方案具有较低的治疗无效率和疾病复发率。因此，替加环素和米诺环素可作为治疗布鲁菌病的候选用药。本文就布鲁菌病传统治疗方案以及替加环素和米诺环素的抗菌效果进行综述。     

替加环素治疗多重耐药菌感染的药物监测

随着抗菌药物在临床中的广泛应用,多重耐药(multidrug-resistant, MDR)菌株日益增多且缺乏有效的治疗药物,已成为公共卫生领域的严重问题。替加环素作为新一代甘氨酰四环素类抗生素,对耐碳青霉烯类鲍曼不动杆菌、耐碳青霉烯类肠杆菌科细菌、耐甲氧西林金黄色葡萄球菌(methicilinresistant Staphylococcus aureus, MRSA)等多重耐药菌具有较高的抗菌活性,其临床应用备受关注。一方面,在治疗多重耐药菌感染时,替加环素在临床中的治疗方案及使用剂量缺乏统一的定论,仍是目前研究的热点;另一方面,替加环素的药代动力学参数受到不同疾病及同种疾病病程发展不同阶段的病理生理变化的影响。所以,开展替加环素的药代动力学/药效学(pharmacokinetic/pharmacodynamic, PK/PD)研究及对多重耐药菌感染患者进行治疗药物监测(therapeutic drug monitoring, TDM)并探索最佳PK/PD参数实属必要。本文将对当前使用替加环素治疗多重耐药菌感染的疗效及其TDM指标作一综述。     

查尔酮类化合物抗肿瘤作用靶点的研究进展

查尔酮是一种天然化合物,为多种药用植物的有效成分,国内外已经陆续报道了其抗肿瘤活性。查尔酮类化合物抗肿瘤作用靶点较为广泛,但缺乏系统性的文献综述。因此,该文将针对查尔酮类化合物作为潜在的抗肿瘤药物靶向抑制IκB激酶、硫氧还蛋白还原酶、微管蛋白、血管表皮生长因子、p53通路来发挥抗肿瘤作用的研究进行综述,以期为肿瘤的治疗提供更多的理论参考。     

β-桧木醇联合替加环素对tet(X4)阳性大肠杆菌的体外协同抗菌作用

质粒介导tet(X4)基因的出现和流行,严重影响替加环素(tigecycline)对临床多重耐药细菌感染的治疗效果,急需寻找有效的佐剂遏制替加环素耐药性。本研究采用微量棋盘稀释法、时间-杀菌曲线测定β-桧木醇(β-thujaplicin)和替加环素的体外联合抗菌表征,通过测定细菌细胞膜通透性、细菌胞内活性氧(reactive oxygen species,ROS)含量、铁含量以及替加环素含量等指标,来探究β-桧木醇和替加环素联合使用对tet(X4)基因阳性大肠杆菌(Escherichia coli)的抗菌作用机制。结果表明,β-桧木醇联合替加环素对tet(X4)基因阳性大肠杆菌具有体外协同抗菌效果,且β-桧木醇在抗菌作用浓度范围内无显著溶血性和细胞毒性。机制研究发现,β-桧木醇能显著增大细菌细胞膜的通透性,降低细菌胞内铁含量,干扰铁稳态,诱导细胞内ROS显著增加,从而发挥抗菌效果。进一步研究发现,β-桧木醇可通过干扰细菌铁代谢和增大细菌细胞膜通透性,协同增强替加环素的抗菌效果。本研究结果为β-桧木醇联合替加环素治疗tet(X4)基因阳性大肠杆菌感染提供了理论和实践基础。     

耐碳青霉烯类肠杆菌科细菌体外抗菌活性分析

目的了解临床分离的59株碳青霉烯酶类抗生素耐药的肠杆菌科细菌(CRE)体外药敏情况。方法采用法国生物梅里埃公司VITEK-2Compact全自动细菌分析鉴定系统进行细菌鉴定及药敏,MALDI-TOF MS确认。琼脂稀释法测定临床常用抗生素的最低抑菌浓度。结果分离的菌株以肺炎克雷伯菌为主。59株CRE除对亚胺培南和美罗培南耐药率100.0%外,对哌拉西林/他巴唑坦和阿莫西林/克拉维酸同样完全耐药。头孢他啶、头孢噻肟、氨曲南耐药率分别为91.5%、98.5%和94.8%。阿米卡星有较好的抗菌活性,耐药率为44.8%。替加环素耐药率最低,为22.0%。结论 CRE耐药率较高,头孢类、青霉素类及其复合制剂单独用药不适合作为本地区CRE菌株抗菌药物,需联合用药。替加环素目前可作为CRE理想用药,阿米卡星也可作为次选。     

纳米药物递送系统在基于化疗的联合治疗中的研究进展

肿瘤是一种病理过程复杂的疾病。大多数肿瘤患者接受化疗和放疗，但这些治疗通常只对部分有效，并产生各种严重的副作用。因此，有必要开发新的治疗策略。联合治疗是目前肿瘤治疗的热点，联合用药引起的多种协同作用是提高抗肿瘤活性的关键。纳米药物递送系统的出现对临床治疗产生了深远的影响。药物的体内递送常不能达到令人满意的治疗效果，而纳米药物递送系统可以实现肿瘤靶向给药，在提高抗肿瘤效果的同时降低药物的毒副作用。本文介绍了多种基于化疗的联合治疗方法，重点阐述了纳米药物递送系统在基于化疗的联合治疗中的运用，并对该领域面临的挑战和未来发展方向进行了展望。     

白花丹素抗肿瘤作用机制的研究进展

恶性肿瘤一直是生物医学中的难题，利用放射疗法或化学疗法治疗肿瘤常会引发如呕吐、恶心等不良反应。因此，寻找安全有效治疗肿瘤的替代药物源非常重要。白花丹素(plumbagin, PLB)是从中草药白花丹根部提取出来的一种生物活性化合物，在肿瘤治疗中具有重要作用，并且有较好的抗癌活性。因此，本文将从肿瘤细胞的增殖、凋亡、转移和侵袭、血管生成、铁死亡过程以及化疗敏感性等六个方面对白花丹素的抗肿瘤作用及相关分子机制的研究进行综述，以期为基于白花丹素的抗肿瘤药物研发和临床应用提供科学参考。     

环吡酮胺对食管鳞癌细胞增殖和迁移的影响

环吡酮胺已被确认为潜在的抗肿瘤药物,但其对于食管鳞癌细胞的影响及其作用机制尚不完全明确。本研究应用MTT法确定了环吡酮胺对食管鳞癌细胞Eca109的IC_(50)和对细胞增殖能力的影响。通过Transwell迁移实验检测环吡酮胺对食管鳞癌细胞迁移能力的影响;Seahorse生物能量分析仪检测食管鳞癌细胞耗氧率;应用流式细胞术分析环吡酮胺对食管鳞癌细胞内活性氧、线粒体活性氧、线粒体膜电位、细胞周期以及细胞凋亡的影响;应用Western blot技术检测环吡酮胺对食管鳞癌细胞线粒体呼吸链酶复合物亚基、细胞周期以及细胞凋亡相关蛋白的影响。该研究显示,环吡酮胺能够破坏线粒体功能、促进食管鳞癌细胞内和线粒体活性氧的累积、诱导细胞凋亡、同时阻滞细胞周期在G1期,进而抑制食管鳞癌细胞的增殖和迁移。该研究结果提示,环吡酮胺具有一定的抑制食管鳞癌细胞增殖和迁移的能力,是一种潜在的治疗食管鳞癌的药物。     

紫草素在消化系统肿瘤中的抗癌机制研究进展

消化系统肿瘤是威胁我国居民生命健康的重要杀手,其发病率和死亡率均占全部肿瘤的50%左右,研发高效安全的抗肿瘤药物是治疗消化系统肿瘤的基础。植物提取物是抗肿瘤药物的重要来源,紫草素(Shikonin)是一种存在于紫草科植物根茎中的药物成分,它对消化系统肿瘤细胞具有显著的杀伤效果。本文通过检索最近10年紫草素在消化系统肿瘤中发挥抗癌作用的相关文献,对紫草素及其衍生物在消化系统肿瘤中的抗癌机制进行系统归纳整理,并分析了今后紫草素应用于临床治疗消化系统肿瘤的研究方向,为进一步探索紫草素在消化系统肿瘤中的抗癌机制研究和新药研发提供理论依据。     

Ganoderma atrum polysaccharide induces anti-tumor activity via the mitochondrial apoptotic pathway related to activation of host immune response

Ganoderma atrum polysaccharide (PSG-1), the major active ingredient isolated from Ganoderma atrum, has been suggested as a candidate for cancer therapy. The aim of this study was to investigate the anti-tumor effect of PSG-1 using sarcoma 180 (S-180) transplanted mice and further to examine the molecular mechanisms of PSG-1-induced anti-tumor effect. Results showed that PSG-1 significantly inhibited tumor growth in S-180-bearing mice. PSG-1-induced tumor apoptosis was associated with the alteration of Bcl-2 family proteins, increase of reactive oxygen species generation, loss of mitochondrial membrane potential (Δψ(m) ), release of cytochrome c from the mitochondria into cytosol, and activation of caspase-3 and -9. Elevation of immune function was also shown during PSG-1-induced tumor apoptosis, as evidenced by increase of spleen and thymus indexes, lymphocyte proliferation, concentrations of tumor necrosis factor (TNF)-α, and interleukin-2 in serum. Furthermore, the combined treatment of PSG-1 and cyclophosphamide (CTX) results in an enhancement of the anti-tumor effect of CTX alone via increased host immune response. These results suggested that PSG-1 had a potent anti-tumor activity by induction of tumor apoptosis through mitochondrial pathways, and immunoenhancement effect of PSG-1 was related to its anti-tumor effect. In addition, PSG-1 enhanced CTX-induced anti-tumor activity in S-180-bearing mice.     

A Novel Formulation of Tigecycline Has Enhanced Stability and Sustained Antibacterial and Antileukemic Activity

Tigecycline is a broad-spectrum, first-in-class glycylcycline antibiotic currently used to treat complicated skin and intra-abdominal infections, as well as community-acquired pneumonia. In addition, we have demonstrated that tigecycline also has in vitro and in vivo activity against acute myeloid leukemia (AML) due to its ability to inhibit mitochondrial translation. Tigecycline is relatively unstable after reconstitution, and this instability may limit the use of the drug in ambulatory infusions for the treatment of infection and may prevent the development of optimal dosing schedules for the treatment of AML. This study sought to identify a formulation that improved the stability of the drug after reconstitution and maintained its antimicrobial and antileukemic activity. A panel of chemical additives was tested to identify excipients that enhanced the stability of tigecycline in solution at room temperature for up to one week. We identified a novel formulation containing the oxygen-reducing agents ascorbic acid (3 mg/mL) and pyruvate (60 mg/mL), in saline solution, pH 7.0, in which tigecycline (1 mg/mL) remained intact when protected from light for at least 7 days. This formulation also preserved the drug''s antibacterial and antileukemic activity in vitro. Moreover, the novel formulation retained tigecycline''s antileukemic activity in vivo. Thus, we identified and characterized a novel formulation for tigecycline that preserves its stability and efficacy after reconstitution.     

豹蛙酶研究进展

豹蛙酶是一种抗肿瘤药物,属于核糖核酸酶A超家族,它的核糖核酸酶活性低,细胞毒性较强,在体内外对多种肿瘤具有显著杀伤作用,是目前全球正在重点研究的100种新药之一。豹蛙酶用于恶性间皮瘤的治疗目前处于Ⅲ期临床研究阶段,用于非小细胞肺癌和其他固体肿瘤的治疗也处于临床Ⅰ期或Ⅱ期研究阶段。豹蛙酶通过多种机制导致肿瘤细胞凋亡,抗病毒作用是其进一步研究开发的重点。     

Desferal inhibits breast tumor growth and does not interfere with the tumoricidal activity of doxorubicin

Desferal is a clinically approved iron chelator used to treat iron overload. Doxorubicin is an anthracycline cancer chemotherapy drug used in the treatment of breast cancer. It can undergo redox cycling in the presence of iron to produce reactive oxygen species. The oxidant-generating activity of doxorubicin is thought to be responsible for the cardiotoxic side effects of the drug, but it is unclear whether it is also required for its anti-tumor activity. To test whether an iron-chelating antioxidant would interfere with the tumor-killing activity of doxorubicin, nude mice were transplanted with xenografts of human breast cancer MDA-MB 231 cells and then treated with doxorubicin and/or desferal. Not only did desferal not interfere with the anti-tumor activity of doxorubicin, it inhibited tumor growth on its own. In vitro studies confirmed that desferal inhibits breast tumor growth. However, it did not induce apoptosis, nor did it induce cell cycle arrest. Instead, desferal caused cytostasis, apparently through iron depletion. The cytostatic activity of desferal was partially ameliorated by pretreatment with iron-saturated transferrin, and transferrin receptor expression on breast cancer cells nearly doubled after exposure to desferal. In contrast to its effect on tumor cells, desferal did not inhibit growth of normal breast epithelial cells. The data indicate that the anti-tumor activity of doxorubicin is not dependent on iron-mediated ROS production. Furthermore, desferal may have utility as an adjunctive chemotherapy due to its ability to inhibit breast tumor growth and cardiotoxic side effects without compromising the tumor-killing activity of an anthracycline chemotherapy drug.     

Hsp90 facilitates acquired drug resistance of tumor cells through cholesterol modulation however independent of tumor progression

Acquired multidrug resistance of cancer cells challenges the chemotherapeutic interventions. To understand the role of molecular chaperone, Hsp90 in drug adapted tumor cells, we have used in vitro drug adapted epidermoid tumor cells as a model system. We found that chemotherapeutic drug adaptation of tumor cells is mediated by induced activities of both Hsp90 and P-glycoprotein (P-gp). Although the high-affinity conformation of Hsp90 has correlated with the enhanced drug efflux activity, we did not observe a direct interaction between P-gp and Hsp90. The enrichment of P-gp and Hsp90 at the cholesterol-rich membrane microdomains is found obligatory for enhanced drug efflux activity. Since inhibition of cholesterol biosynthesis is not interfering with the drug efflux activity, it is presumed that the net cholesterol redistribution mediated by Hsp90 regulates the enhanced drug efflux activity. Our in vitro cholesterol and Hsp90 interaction studies have furthered our presumption that Hsp90 facilitates cholesterol redistribution. The drug adapted cells though exhibited anti-proliferative and anti-tumor effects in response to 17AAG treatment, drug treatment has also enhanced the drug efflux activity. Our findings suggest that drug efflux activity and metastatic potential of tumor cells are independently regulated by Hsp90 by distinct mechanisms. We expose the limitations imposed by Hsp90 inhibitors against multidrug resistant tumor cells.     

Anti-tumor and anti-metastatic roles of cordycepin,one bioactive compound of Cordyceps militaris

Public interest in complementary and alternative medicine has been increased worldwide, due to its wide applications in cancer prevention and treatment. Cordycepin is one of the most common and crucial types of complementary and alternative medicine. Cordycepin (3′-deoxyadenosine), a derivative of adenosine, was first isolated from medicine drug Cordyceps militaris. Cordycepin has been widely used as one compound for antitumor, which has been found to exert antiangiogenic, anti-metastatic, and antiproliferative effects, as well as inducing apoptosis. However, the mechanism of its anti-tumor activity is not well known. This review will clarify anti-tumor mechanisms of Cordycepin, which regulate signaling pathways related with tumor growth and metastasis. Cordycepin inhibit tumor growth via upregulating tumor apoptosis, inducing cell cycle arrest and targeting cancer stem cells (CSCs). Cordycepin regulates tumor microenvironment via suppressing tumor metastasis-related pathways. Thus, Cordycepins may be one of important supplement or substitute medicine drug for cancer treatment.     

Antibiotic tigecycline inhibits cell proliferation,migration and invasion via down-regulating CCNE2 in pancreatic ductal adenocarcinoma

Recently, many researches have reported that antibiotic tigecycline has significant effect on cancer treatment. However, biomedical functions and molecular mechanisms of tigecycline in human pancreatic ductal adenocarcinoma (PDAC) remain unclear. In the current study, we tried to assess the effect of tigecycline in PDAC cells. AsPC-1 and HPAC cells were treated with indicated concentrations of tigecycline for indicated time, and then, MTT, BrdU and soft agar assay were used to test cell proliferation. The effect of tigecycline on cell cycle and cellular apoptosis was tested by cytometry. Migration and invasion were detected by wound healing assay and transwell migration/invasion assay. Expressions of cell cycle-related and migration/invasion-related protein were determined by using Western blot. The results revealed that tigecycline observably suppressed cell proliferation by inducing cell cycle arrest at G0/G1 phase and blocked cell migration/invasion via holding back the epithelial-mesenchymal transition (EMT) process in PDAC. In addition, tigecycline also remarkably blocked tumorigenecity in vivo. Furthermore, the effects of tigecycline alone or combined with gemcitabine in vitro or on PDAC xenografts were also performed. The results showed that tigecycline enhanced the chemosensitivity of PDAC cells to gemcitabine. Interestingly, we found CCNE2 expression was declined distinctly after tigecycline treatment. Then, CCNE2 was overexpressed to rescue tigecycline-induced effect. The results showed that CCNE2 overexpression significantly rescued tigecycline-inhibited cell proliferation and migration/invasion. Collectively, we showed that tigecycline inhibits cell proliferation, migration and invasion via down-regulating CCNE2, and tigecycline might be used as a potential drug for PDAC treatment alone or combined with gemcitabine.     

Tigecycline is modified by the flavin-dependent monooxygenase TetX

The clinical use of tetracycline antibiotics has decreased due to the emergence of efflux and ribosomal protection-based resistance mechanisms. Currently in phase III clinical trials, the glycylcycline derivative tigecycline (GAR-936) containing a 9-tert-butylglycylamido group is part of a new generation of tetracycline antibiotics developed during the 1990s. Tigecycline displays a broad spectrum of antibacterial activity and circumvents the efflux and ribosomal protection resistance mechanisms. The TetX protein is a flavin-dependent monooxygenase that modifies first and second generation tetracyclines and requires NADPH, Mg(2+), and O(2) for activity. We report that tigecycline is a substrate for TetX and that bacterial strains containing the tet(X) gene are resistant to tigecycline. The resistance is due to the modification of tigecycline by TetX to form 11a-hydroxytigecycline, which we have shown has a weakened ability to inhibit protein translation compared with tigecycline. We have explored the basis of this decreased ability to block translation and found that hydroxylation occurs in the region of the molecule important for coordinating magnesium. 11a-Hydroxytigecycline forms a weaker complex with magnesium than tigecycline; the crystal structure of tetracycline in complex with the ribosome has shown that magnesium coordination is critical for binding tetracycline. Although tet(X) has not been isolated from any clinically resistant strains, our report demonstrates the first enzymatic resistance mechanism to tigecycline and provides an alert for the surveillance of resistant strains that may contain tet(X).     

Flubendazole induces mitochondrial dysfunction and DRP1-mediated mitophagy by targeting EVA1A in breast cancer

Breast cancer is still one of the most common malignancies worldwide and remains a major clinical challenge. We previously reported that the anthelmintic drug flubendazole induced autophagy and apoptosis via upregulation of eva-1 homolog A (EVA1A) in triple-negative breast cancer (TNBC) and was repurposed as a novel anti-tumor agent. However, the detailed underlying mechanisms remain unclear and need further investigation. Here, we found that flubendazole impairs the permeability of the mitochondrial outer membrane and mitochondrial function in breast cancer. Meanwhile, flubendazole increased dynamin-related protein (DRP1) expression, leading to the accumulation of PTEN induced putative kinase 1 (PINK1) and subsequent mitochondrial translocation of Parkin, thereby promoting excessive mitophagy. The resultant excessive mitophagy contributed to mitochondrial damage and dysfunction induced by flubendazole, thus inhibiting breast cancer cells proliferation and migration. Moreover, we demonstrated that excessive DRP1-mediated mitophagy played a critical role in response to the anti-tumor effects of EVA1A in breast cancer. Taken together, our results provide new insights into the molecular mechanisms in relation to the anti-tumor activities of flubendazole, and may be conducive to its rational use in potential clinical applications.Subject terms: Breast cancer, Pharmacology