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We aimed to determine the safety of direct oral anticoagulants (DOACs) for stroke prevention and treatment in patients with atrial fibrillation (AF). A systematic search of four databases (PubMed, EMBASE, Web of Science, and Cochrane Library) was performed to identify randomized controlled trials (RCTs) reporting severe bleeding events in patients taking DOACs or vitamin K antagonists (VKAs). In this frequency-based network meta-analysis, odds ratios and 95% confidence intervals were used for reporting. Based on the surface under the cumulative ranking curves (SUCRA), the relative ranking probability of each group was generated. Twenty-three RCTs met the inclusion criteria, and a total of 87,616 patients were enrolled. The bleeding safety of DOACs for stroke prevention and treatment in patients with AF was ranked from highest to lowest as follows: fatal bleeding: edoxaban (SUCRA,80.2), rivaroxaban (SUCRA,68.3), apixaban (SUCRA,48.5), dabigatran (SUCRA,40.0), VKAs (SUCRA,12.9); major bleeding: dabigatran (SUCRA,74.0), apixaban (SUCRA,71.5), edoxaban (SUCRA,66.5), rivaroxaban (SUCRA,22.7), VKAs (SUCRA,15.4); gastrointestinal bleeding: apixaban (SUCRA,55.9), VKAs (SUCRA,53.7), edoxaban (SUCRA,50.5), rivaroxaban (SUCRA,50.4), dabigatran (SUCRA,39.5); intracranial hemorrhage: dabigatran (SUCRA,84.6), edoxaban (SUCRA,74.1), apixaban (SUCRA,65.8), rivaroxaban (SUCRA,24.4), VKAs (SUCRA,1.1). Based on current evidence, for stroke prevention and treatment in patients with AF, the most safe DOAC is edoxaban in terms of fatal bleeding; dabigatran in terms of major bleeding and intracranial hemorrhage and apixaban in terms of gastrointestinal bleeding. However, given the nature of indirect comparisons, more high-quality evidence from head-to-head comparisons is still needed to confirm them.

Wormlike micelles (or reverse wormlike micelles) are flexible cylindrical chains that are normally formed in water (or a nonpolar organic solvent) at 25.0 °C or above; the formation of wormlike micelles at lower temperatures is rare. Here, we have reported wormlike micelles formed at low temperature using an ionic liquid surfactant (1-octadecyl-3-nonyl imidazolium bromide) in polar organic solvents (including 1,3-propanediol, 1,2-propylene glycol, N,N-dimethylformamide, and glycerol/1,2-propylene glycol mixture) in the absence of any additives. The viscoelasticity and morphology of the wormlike micelles were studied using rheology, small-angle X-ray scattering, and cryo-transmission electron microscopy. The viscoelastic properties of the wormlike micelles in polar solvents are affected by the solvent type (or the weight ratio of glycerol to 1,2-propylene glycol), surfactant concentration, and temperature. Moreover, the G' and G'' crossover twice in the dynamic curves, which is different from the case in water. The first crossover (at low frequency) corresponds to the relaxation time for the alkyl chains to disentangle from the transient network, and the second crossover (at high frequency) is related to the segmental motion of the chains. Furthermore, the tribological performance of these wormlike micelles is investigated at low temperature. It is found that the protective film (formed by the physical adhesion of the wormlike micelles on the surface of friction disk pair) and the tribochemical reaction together lead to good antifriction and antiwear performance, which indicates the application prospects of these wormlike micelles in low-temperature lubrication.

Chemoresistance has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome. Long noncoding RNAs play important roles in breast cancer tumorigenesis and chemoresistance. However, the involvement and regulation of lncRNAs in breast cancer chemoresistance are not completely understood. Here, we reported that Linc00839 was localized in the nucleus and upregulated in chemoresistant breast cancer cells and tissues, and high level of Linc00839 was associated with a poor prognosis. Knockdown of Linc00839 significantly suppressed proliferation, invasion, and migration, sensitized cells to paclitaxel in vitro and inhibited transplant tumor development in vivo. Mechanistically, we found that Myc could directly bind to the promoter region of Linc00839 and activate its transcription. Furthermore, Linc00839 overexpression increased the expression of Myc and the RNA‐binding protein Lin28B and activated the PI3K/AKT signaling pathway. We also discovered that Lin28B positively interacted with Linc00839 and was upregulated in breast cancer tissues. Taken together, for the first time, we showed that Linc00839 was activated by Myc and promoted proliferation and chemoresistance in breast cancer through binding with Lin28B. These findings provide new insight into the regulatory mechanism of Linc00839 and propose a Myc/Linc00839/Lin28B feedback loop that could be used as a novel therapeutic target for breast cancer., Linc00839 displayed a remarkable trend towards increasing expression levels in BC resistant cells and tissue samples. The upregulation of Linc00839 was transcriptionally activated by the crucial oncogene Myc, and it was able to regulate Myc and Lin28B protein expression. Linc00839 promoted cell proliferation and chemoresistance by enhancing the activity of the PI3K/AKT pathway.

Exosomes are nanosized vesicles, derived from the endolysosomal compartment of cells and can shuttle diverse biomolecules such as nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their origin cells. Delivery of these cargoes to recipient cells enables exosomes to influence diverse cellular functions. As one of the most abundant immune cells in the tumor microenvironment, tumor-associated macrophages (TAMs) are educated by the tumor milieu, which is rich in cancer cells and stroma components, to exert functions such as the promotion of tumor growth, immunosuppression, angiogenesis, and cancer cell dissemination. Herein, we focus on exosomes-mediated intercellular communication between tumor cells and TAM in the tumor microenvironment, which may provide new targets for anti-tumor treatment. In this review, we highlight the most recent studies on the effect of tumor/macrophage-derived exosomes on macrophage/tumor function in different cancer types.

Background: The E3 ligase SIAH1 is deregulated in human cancers and correlated with poor prognosis, but its contributions to chemoresistance in epithelial ovarian cancer (EOC) are not evident. Methods: SIAHI, RPS3, NF-κB (P65), FLAG and GFP protein levels were assessed by western blotting (WB) or immunohistochemistry (IHC). The mRNA levels were revealed by qRT-PCR. Colocalization of RPS3 and SIAH1 was detected by confocal microscopy and co-immunoprecipitation (CO-IP). RPS3 ubiquitination levels were detected by immunoprecipitation (IP). Cell functional experiments were performed and A2780 xenograft models were employed to expose the latent mechanisms of the SIAH1-RPS3-NF-κB axis as well as the role of SIAH1 in inhibiting chemoresistance in vitro and in vivo.Results: We show that SIAH1 is decreased in EOC tumour tissues and cell lines and negatively correlated with RPS3 level. SIAH1 overexpression suppresses tumour cell growth, colony formation, invasion, metastasis, and cisplatin resistance in vivo and in vitro. SIAH1 promoted RPS3 ubiquitination and degradation using the RING-finger domain, which was required for RPS3 localization to the cytoplasm for subsequent NF-κB inactivation, thereby conferring chemosensitivity. Moreover, ectopic expression of RPS3 or depletion of RPS3 ubiquitination mediated by SIAH1 via the K214R mutant significantly impaired cisplatin-induced tumour suppression in cells stably expressing SIAH1. Conclusions: Our findings reveal a tumour suppressor function of SIAH1 and provide evidence that the SIAH1-RPS3-NF-κB axis may act as an appealing strategy to tackle treatment resistance in EOC.

BACKGROUND This study was conducted to observe the influence of different time intervals between prior cervical conization and posterior hysterectomy on postoperative infection in female patients with cervical intraepithelial neoplasia or cancer. MATERIAL AND METHODS Medical records of 170 patients who underwent hysterectomy following cervical conization between November 2010 and September 2016 at the Zhenjiang 4th Hospital were reviewed. According to the interval between hysterectomy and cervical conization, patients were classified into 1-2-week, 4-5-week, and 6-week groups. The outcomes of 46 patients who underwent conization with iodoform gauze inside the vagina were observed. RESULTS The total postoperative infection rate after hysterectomy was 25.3% (43/170). The expression levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and high mobility group box 1 (HMGB1) in the cervical secretions and tissues were found to gradually increase, peaking at 2 weeks after conization, then significantly decreasing 3-6 weeks onwards. Compared with the 1-2-week group, the 4-5-week and 6-week groups exhibited significantly lower infection rates (2/42, 4.8%, 4-5-week group; 0%, 0/33, 6-week group; vs. 41/95, 43.2%, 1-2-week group; p

TIPE2 participates in multiple types of cancer development. However, its mechanism underlying chemoresistance in osteosarcoma has not been elucidated. Herein, we observed the expression of TIPE2 and MDR1 in cis-platin-resistant osteosarcoma tissues and cell lines. Compared to their matched sensitive cell lines and tissues, TIPE2 was downregulated while MDR1 expression was increased. Further investigation showed that overexpression of TIPE2 effectively inhibited MDR1 expression and greatly sensitized osteosarcoma cells to cis-platin, both in vivo and in vitro. Mechanistically, TIPE2 inhibited the transcription of the MDR1 promoter by interfering with the TAK1-NF-κB and -AP-1 pathways. Overall, our results elucidated for the first time that TIPE2 sensitizes osteosarcoma cells to cis-platin through downregulation of MDR1 and may be a novel target in osteosarcoma therapy.

Background The Na+/H+ exchanger (NHE1) plays a crucial role in cancer cell proliferation and metastasis. However, the mechanism underlying chemotherapeutic resistance in cancer cells has not been completely elucidated. The NHE1 inhibitor cariporide has been demonstrated to inhibit human cancer cell lines. The goal of this study was to provide new sights into improved cancer cell chemosensitivity mediated by cariporide with activation of the apoptosis pathway. Methods The NHE1 expression levels were first evaluated using the online database Oncomine and were determined by RT-PCR and western blot in vitro and in vivo. Cell proliferation was assessed In vitro through a CCK-8 assay, and apoptosis was analyzed by flow cytometry. An in vivo analysis was performed in BALB/c nude mice, which were intraperitoneally injected with MCF-7/ADR cells. Results NHE1 levels were significantly higher in breast cancer tissue than adjacent tissue, as well as in resistant cancer cells compared to sensitive cells. Cariporide induced the apoptosis of MCF-7/ADR cells and was associated with the intracellular accumulation of doxorubicin and G0/G1 cell cycle arrest. Moreover, cariporide decreased MDR1 expression and activated cleaved caspase-3 and caspase-9, promoting caspase-independent apoptosis in vitro. In vivo, cariporide significantly improved doxorubicin sensitivity in a xenograft model, enhancing tumor growth attenuation and diminishing tumor volume. Conclusions Our results demonstrate that cariporide significantly facilitates the sensitivity of breast cancer to doxorubicin both in vitro and in vivo. This finding suggests that NHE1 may be a novel adjuvant therapeutic candidate for the treatment of resistant breast cancer. Electronic supplementary material The online version of this article (10.1186/s12885-019-5397-7) contains supplementary material, which is available to authorized users.

Background How exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of drug resistance in the context of the hypoxic tumor microenvironment in epithelial ovarian cancer (EOC) remains poorly understood. Methods The miRNA levels were detected by qRT-PCR. Protein levels of HIF-1α, CD163 and PTEN-PI3K/AKT pathway were assessed by Western blot (WB) and Immunohistochemistry (IHC). Exosomes were isolated, and then confirmed by Transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA) and WB. Internalization of macrophages-secreted exosomes in EOC cells was detected by Confocal microscope. Subsequently, Dual-luciferase reporter assay verified PTEN was the target of miR-223. Gain- and loss-of-function experiments, rescue experiments, and SKOV3 xenograft models were performed to uncover the underlying mechanisms of miR-223 and PTEN-PI3K/AKT pathway, as well as the exosomal miR-223 in inducing multidrug resistance in vitro and in vivo. Results Here, we showed hypoxic EOC cells triggered macrophages recruitment and induced macrophages into a tumor-associated macrophage (TAM)-like phenotype; exosomes derived from hypoxic macrophages enhanced the malignant phenotype of EOC cells, miR-223 was enriched in exosomes released from macrophages under hypoxia, which could be transferred to the co-cultivated EOC cells, accompanied by enhanced drug resistant of EOC cells. Besides, results from a functional assay revealed that exosomal miR-223 derived from macrophages promoted the drug resistance of EOC cells via the PTEN-PI3K/AKT pathway both in vivo and in vitro. Furthermore, patients with high HIF-1a expression had statistically higher CD163+ cell infiltration and intertumoral levels of miR-223. Finally, circulating exosomal miR-223 levels were closely related to the recurrence of EOC. Conclusions These data indicate a unique role of exosomal miR-223 in the cross-talk between macrophages and EOC cells in chemotherapy resistance, through a novel exosomal miR-223/PTEN-PI3K/AKT signaling pathway. Electronic supplementary material The online version of this article (10.1186/s13046-019-1095-1) contains supplementary material, which is available to authorized users.

To date, there is limited information regarding the interaction between zwitterionic surfactants and protein. In this study, the interaction between the sulfobetaine surfactants, N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (SDDAB) and N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (SHDAB), and protein was studied by multiple techniques. Bromelain (BM) and polyphenol oxidase (PPO) were selected as model proteins. Although BM and PPO showed a very limited effect on the surface tension–concentration curve of the sulfobetaine surfactant, the sulfobetaine surfactant increased the fluorescence intensity of the enzyme, and the NMR peaks of both the surfactant and the enzyme widened obviously once they were mixed. Moreover, the sulfobetaine surfactants showed an obvious effect on the enzyme activity, and the effect of sulfobetaine surfactants on the enzyme activity was different from that of cationic and anionic surfactants. The sulfobetaine surfactants enhanced PPO activity once their concentration reached the critical micelle concentration (cmc), while they increased the BM activity obviously at a content much lower than cmc; the activity of both enzymes was eventually doubled or more. Besides, the sulfobetaine surfactants enhanced the BM activity at a broad range of temperature, pH and salt levels, while they promoted the PPO activity only at a pH lower than 8 and temperature lower than 50 °C.

Imidazolium-based surface active ionic liquids (Im-SAILs) are based on imidazolium salts with long hydrophobic alkyl chains. Due to the delocalized electrons on the imidazole ring and the hydrogen bonding between imidazole rings, Im-SAILs can exhibit novel aggregation behavior that differs from that of conventional surfactants. In both the absence and presence of a solvent (such as water, organic solvents, and ionic liquids), Im-SAILs exhibit rich self-aggregation behavior and form various types of assemblies, including spherical micelles, wormlike micelles, nanosheets, nanorods, nanospheres, nanotubes, nanoclusters, vesicles, vesicle clusters, liquid crystals, planar bilayers and gels. Additives (including conventional surfactants, polymers, metal oxides, amino acids, and proteins) enhance the aggregation of Im-SAILs through the synergistic effects of multiple intermolecular interactions, such as electrostatic, hydrophobic, hydrogen bonding, and cation-π interactions; in some cases, the resulting assemblies can even respond to external stimuli, such as pH, temperature, light, organic solvent, and others. By effectively utilizing the versatile “designability” of ionic liquids and/or choosing suitable additives, the controllable self-assembly of new ordered molecular aggregates can be realized. These strategies are expected to lead to the discovery of novel “soft” materials and the development of aggregates with important and/or novel applications. Therefore, in this review, we first summarize the recent advances related to the assembly behavior of Im-SAILs. The roles of the surfactant and counter-ion structures are analyzed. The assembly of Im-SAILs in the presence of additives, including conventional surfactants, polymers, metal oxides, amino acids, and proteins, is then reviewed. At the end of this review, a prospective future involving Im-SAILs are discussed.

Myeloid-derived suppressor cells (MDSC) constitute the major cell population that regulates immune responses. They are known to accumulate in tumors, chronic inflammatory and autoimmune diseases. Previous data indicate that high mobility group box 1(HMGB1) facilitates MDSC differentiation from bone marrow, suppresses NK cells, CD4+ and CD8+ T cells and is involved in cancer development. However, it remains unclear what potential mechanisms of HMGB1 facilitate MDSC differentiation. In the present work, we clearly demonstrate that HMGB1 secreted by cancer cells is N-glycosylated at Asn37, which facilitates monocytic (M)-MDSC differentiation from bone marrow via the p38/NFκB/Erk1/2 pathway and also contributes to conversion of monocytes into MDSC-like cells; HMGB1 blockade by a monoclonal antibody against the HMGB1 B box obviously reduced the accumulation of M-MDSC in tumor-bearing mice, delaying tumor growth and development; additionally, MDSC expansion and HMGB1 up-regulation were also found in breast cancer patients. All these data indicate that HMGB1 might be a potential tumor immunotherapy target.

Structrual and dynamic properties of thiophene (C4H4S) in supercritical carbon dioxide were studied using Car-Parrinello molecular dynamics simulations. The geometries and energies optimized for the thiophene-CO2 complex show a stable C-H···O hydrogen bond interactions both in gas phase and in supercritical CO2. The radial distribution functions of CO2 around thiophene in the supercritical phase state show a correlation suggesting C-H···O hydrogen bond and S···C interaction. Local structural properties of the mixtures were investigated by angular-radial distributions and spatial distribution functions. The results show a mutually parallel arrangement between the thiophene plane and CO2 molecules at short distances and a high probability of the thiophene being located in the radial directions of the CO2 molecules. The decay of orientational correlations at 318.15 K shows slower relaxation compared to those of 298.15 K for first and second rank correlations. The vibrations of CO2 and thiophene molecules have been examined through an analysis of the velocity autocorrelation functions of the atoms. The C-H stretching modes of thiophene in the isolated configuration are less red-shifted and have a much narrower frequency range than that in the mixtures.

The objective of the present study was to investigate the role of blood glucose, lipid metabolism, body mass index (BMI), C-reactive protein (CRP) as well as an interleukin (IL)-17/IL-35 imbalance in the pathogenesis of concurrent gestational diabetes mellitus (GDM) and preeclampsia (PE) (DPE). The mRNA expression of forkhead box protein 3 (FoxP3), IL-35 [including Epstein-Barr virus-induced gene 3 (EBI3) and P35 subunits] and IL-17 in the peripheral blood mononuclear cells of patients with DPE (n=30), GDM (n=33), PE (n=33) and normal pregnancy (n=33) were determined by reverse transcription-quantitative polymerase chain reaction. The serum levels of IL-35, IL-17 and CRP were analyzed using ELISA. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) and fasting blood glucose (FBG) were also detected. The levels of low-density lipoprotein (LDL) were calculated using the Friedewald formula. Body weight and height were determined in order to calculate the BMI. It was observed that the levels of FBG were markedly elevated in patients with GDM, PE and DPE. In addition, significantly higher serum TG, TC, LDL and very LDL were detected in patients with GDM, PE and DPE compared with those in subjects with normal pregnancies. By contrast, the concentration of HDL was lower in the patient groups. In addition, higher BMI values were identified in patients with GDM, PE and DPE. A decreased expression of FoxP3, P35 and EBI3 mRNA, and an elevated expression of IL-17 in PBMCs was detected in patients with GDM, PE and DPE. In addition, higher serum levels of IL-17 and CRP, as well as lower levels of IL-35, were observed. Furthermore, in patients with DPE, positive correlations of diastolic blood pressure with IL-17 levels, BMI and TG, as well as IL-17 levels with BMI and proteinuria were identified. In conclusion, the present study indicated that abnormal maternal lipids, hyperglycemia, high BMI, high CRP and IL-17/IL-35 imbalance may have a role in the pathophysiology of DPE. Therefore, pregnant women and clinicians should be made aware that maternal hyperlipidaemia, hyperglycemia, high BMI, high CRP levels and IL-17/IL-35 imbalance may lead to DPE.

Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel-resistant ovarian cancer patients and cell lines had decreased miR-145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR-145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR-145, resulting in restoration of P-gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR-145. Intriguingly, demethylation with 5-aza-dC led to reactivation of miR-145 expression in drug-resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR-145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1.

Increasing evidence suggests that hsa-miR-126 (miR-126) is down-regulated in non-small cell lung cancer (NSCLC) cell lines and the restoration of miR-126 impairs tumor cell proliferation, migration, invasion, and survival by targeting specific molecules. Here, we reported for the first time that miR-126 was involved in regulating the response of NSCLC cells to cancer chemotherapy. After transfected A549 cells with miR-126 mimic or inhibitor, we found that an elevated level of miR-126 was significantly associated with a decreased half maximal inhibitory concentration of adriamycin (ADM) and vincristine, an increased accumulation of ADM, down-regulation of vascular endothelial growth factor A (VEGFA) and multidrug resistance-associated protein 1 (MRP1), and inactivation of the Akt signaling pathway. Furthermore, enhanced expression of miR-126 suppressed the growth of A549 xenograft and inhibited the expression of VEGFA and MRP1. miR-126 could efficiently down-regulate VEGFA expression through the interaction with the VEGFA 3'-untranslated region, whereas restoration of VEGFA could partially attenuate the suppression of MRP1 by miR-126. However, LY294002, an inhibitor of the PI3K/Akt signaling pathway, diminished this effect, suggesting that enhanced expression of miR-126 increased the sensitivity of NSCLC cells to anticancer agents through negative regulation of a VEGF/PI3K/Akt/MRP1 signaling pathway.

There have been no reports describing successful drug resistance reversal in tumors in the clinic until now. Conversion of drug resistance reversal studies to drug resistance prevention studies may assist in the development of more efficient anti-tumor strategies. The present study demonstrates the prevention of doxorubicin-induced drug resistance by tetrandrine on leukemia cells.K562 cells were either solely treated with doxorubicin (0.6 mg/ml) or pretreated with tetrandrine of different concentrations (0.5, 1.0 and 2.0 microg/ml) for 24 h followed by combined-treatment with doxorubicin (0.6 microg/ml).The results showed that doxorubicin treatment only resulted in elevated levels of mdr1 mRNA/P-gp expression. Doxorubicin also induced up-regulation of P-gp functional activities, as intracellular retention of rhodamine was decreased; however, 2.0 microg/ml tetrandrine significantly inhibited the overexpression of doxorubicin-induced mdr1 mRNA/P-gp. Consistently, the functional activity of P-gp was also inhibited, which led to increased intracellular drug retention and the recovery of cell sensitivity to chemotherapeutic drugs in combined treatment groups. Both mRNA and protein levels of NF-kappaB were up-regulated in the cells treated with doxorubicin only. Results from an electrophoretic mobility shift assay and a chromatin immunoprecipitation assay demonstrated the enhanced binding to the promoter region of mdr1 gene compared to the control group. However, tetrandrine could markedly inhibit the doxorubicin-induced expression of NF-kappaB mRNA and protein. In addition, it also attenuated the NF-kappaB DNA-binding activity.In summary, tetrandrine can prevent doxorubicin-induced mdr1 mRNA/P-gp expression and P-gp functions in a dose-dependent manner through a mechanism that may involve inhibition of doxorubicin-induced NF-kappaB mRNA expression and protein activity.

Recent studies have shown that microRNA-21 (miR-21) contributes to tumor resistance to chemotherapy. Interestingly, we have found that berberine could inhibit miR-21 expression in several cancer cell lines. In this study, we investigated whether berberine could modulate the sensitivity of ovarian cancer cells to cisplatin and explored the mechanism. The cisplatin-resistant SKOV3 cells that were incubated with berberine combined with cisplatin had a significantly lower survival than the cisplatin alone group and enhanced cisplatin-induced apoptosis. Berberine could inhibit miR-21 expression and function in ovarian cancer, as shown by an enhancement of its target PDCD4, an important tumor suppressor in ovarian cancer. The results suggested that berberine could modulate the sensitivity of cisplatin via regulating miR-21/PDCD4 axis in the ovarian cancer cells.

Multidrug resistance (MDR) is one of the most important causes of chemotherapy failure and carcinoma recurrence. But the roles of the MDR-associated protein MRP1 in MDR remain poorly understood. Vascular endothelial growth factor (VEGF), one of the most active and specific vascular growth factors, plays a significant role in proliferation, differentiation, and metastasis of cancers. To explore the effect of VEGF on the expression of MRP1, we used recombinant human VEGF to stimulate K562 and BGC-823 cell lines. Quantitative real-time polymerase chain reaction and western blot analysis showed that the expression of MRP1 at both mRNA and protein levels was increased. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide results also showed that VEGF significantly enhanced the IC50 of the cells treated with adriamycin. To explore the underlying regulatory mechanisms, we constructed MRP1 promoter and the luciferase reporter gene recombinant vector. The luciferase reporter gene assay showed that the activity of the MRP1 promoter was markedly increased by VEGF stimulation, while LY294002, an inhibitor of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, reduced this effect. Transcription factor specificity protein 1 (SP1) binding site mutation partially blocked the up-regulation of MRP1 promoter activity by VEGF. In summary, our results demonstrated that VEGF enhanced the expression of MRP1, and the PI3K/Akt signaling pathway and SP1 may be involved in this modulation.

Multidrug resistance (MDR) to chemotherapeutic agents is a major obstacle to successful treatment in breast cancer patients. The aims of this study were to investigate whether miR-137 was involved in the regulation of MDR, and to explore the mechanism of miR-137 on the sensitivity of MCF-7/ADM cells. miR-137 was downregulated in MCF-7/ADM cells, and its expression was found to inversely correlate with Y-box binding protein-1 (YB-1) and P-glycoprotein (P-gp) levels in breast cancer cells. Furthermore, YB-1 was confirmed as a target of miR-137 by luciferase reporter assay and western blot analysis. Moreover, elevated expression of miR-137 reduced the protein expression levels of YB-1 and P-gp, mimicking the effect of YB-1 knockdown in the sensitivity of MCF-7/ADM cells to anticancer agents, whereas restoration of YB-1 diminished this effect. In conclusion, our results demonstrated that miR-137 was involved in MDR in cancer through modulation of P-gp by targeting YB-1, suggesting that miR-137 might be a potential target for preventing and reversing MDR in tumor cells.

Multidrug-resistance is a serious obstacle encountered in leukemia treatment. Recent studies have shown microRNA-21 (miR-21) is overexpressed in several types of cancer and contributes to tumor resistance to chemotherapy. In our previous studies, we found triptolide (TPL) could enhance adriamycin-induced cytotoxicity and apoptosis in K562/A02 cells.In the present study, we investigated the mechanism of TPL on the sensitivity of K562/A02 cells to adriamycin.Cell viability was assessed by methyl thiazolyl tetrazolium (MTT) assay. Expression of mature miR-21 was determined by SYBER green PCR. The miR-21 mimics and inhibitors were chemically synthesized and transfected into K562 cells or K562/A02 cells. PTEN protein levels was determined by western blots. PTEN promoter activity was measured by luciferase assays.TPL (5 nmol/L) increased the sensitivity of K562/A02 to adriamycin. When adriamycin was combined with 5 nmol/L TPL, the mean apoptotic population of K562/A02 cells was increased from 4.3 to 18.5%, respectively. K562/A02 cells showed a significant reduction in miR-21 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) expressions after TPL treatment. K562/A02 cells that were transfected with the miR-21 inhibitor had a significantly higher PTEN protein level than the control. K562 cells that were pre-treated with PTEN siRNA had increased survival rate compared to the control group.Our findings indicated that triptolide modulates the sensitivity of K562/A02 cells to adriamycin by regulating miR-21 expression. Triptolide inhibited miR-21 expression and enhanced PTEN levels in K562/A02 cells.

The aim of this study was to investigate whether miR-181a could modulate the sensitivity of the leukemia drug-resistant cell line K562/A02 to the chemotherapeutic agent daunorubicin (DNR), and explore the mechanism of miR-181a on the DNR sensitivity of K562/A02 cells. MicroRNA microarray and stem-loop reverse transcription-polymerase chain reaction were used to detect the expression of miR-181a. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay was performed to quantify the effect of miR-181a on K562 cells growth and viability. Apoptotic cells were quantitatively detected using Annexin V/FITC and PI apoptosis detection kit. BCL-2 protein expression was measured by western blot. Luciferase reporter vector with the putative BCL-2 3' untranslated region was constructed to explore whether BCL-2 was a direct target gene of miR-181a. BCL-2 siRNA was transfected into the cell to explore the relationship between BCL-2 and DNR resistance. The miR-181a expression level was lower in the K562/A02 cells than in the K562 cells (P< 0.05). K562 cells that were transfected with miR-181a inhibitor had a significantly higher survival than K562 cells, and K562/A02 cells that were transfected with the miR-181a mimic had a significantly lower survival than K562/A02 cells (P< 0.05). miR-181a could enhance DNR-induced apoptosis in K562/A02 cells. BCL-2 siRNA transfected K562/A02 cells had decreased survival compared with the K562/A02 control group. In conclusion, miR-181a could play a role in the development of DNR resistance in K562/A02 cells and the over-expression of miR-181a could sensitize K562/A02 cells to DNR by targeting BCL-2.

Tetrandrine, a bis-benzylisoquinoline alkaloid isolated from the dried root of Hang-Fang-Chi ( Stephania tetrandra S. Moore), has been reported to possess anti-cancer effects on many tumors. In this study, we investigated tetrandrine-induced apoptosis on human gastric cancer BGC-823 cells in vitro and in vivo. The results showed that tetrandrine significantly inhibited cell viability in a dose- and time-dependent manner and induced apoptosis. It increased the apoptosis; upregulation of Bax, Bak, and Bad; and downregulation of Bcl-2 and Bcl-xl in BGC-823 cells. Moreover, tetrandrine increased the activation of caspase-3 and -9, release of cytochrome c, and upregulation of apaf-1, suggesting that tetrandrine-induced apoptosis was related to the mitochondrial pathway. Meanwhile, pretreatment with the pan-caspase inhibitor z-VAD-fmk in BGC-823 cells reduced tetrandrine-induced apoptosis by blocking activation of caspases. Furthermore, tetrandrine effectively inhibited tumor growth via apoptosis induction, which was verified by immunohistochemical analysis in a nude mouse xenograft model. Taken together, we concluded that tetrandrine significantly inhibited the proliferation of gastric cancer BGC-823 cells through mitochondria-dependent apoptosis, which may play a promising role in gastric cancer therapy.