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Reduced drug uptake and elevated drug efflux are two major mechanisms in cancer multidrug resistance (MDR). In the present study, a new multistage O

Although the development of safe and efficient cancer therapeutic agents is essential, this process remains challenging. In this study, a mitochondria-targeted degradable nanoplatform (PDA–MnO2-IR780) for synergistic photothermal, photodynamic, and sonodynamic tumor treatment was investigated. PDA–MnO2-IR780 exhibits superior photothermal properties owing to the integration of polydopamine, MnO2, and IR780. IR780, a photosensitizer and sonosensitizer, was used for photodynamic therapy and sonodynamic therapy. When PDA–MnO2-IR780 was delivered to the tumor site, MnO2 was decomposed by hydrogen peroxide, producing Mn2+ and oxygen. Meanwhile, alleviating tumor hypoxia promoted the production of reactive oxygen species during photodynamic therapy and sonodynamic therapy. Moreover, large amounts of reactive oxygen species could reduce the expression of heat shock proteins and increase the heat sensitivity of tumor cells, thereby improving the photothermal treatment effect. In turn, hyperthermia caused by photothermal therapy accelerated the production of reactive oxygen species in photodynamic therapy. IR780 selectively accumulation in mitochondria also promoted tumor apoptosis. In this system, the mutual promotion of photothermal therapy and photodynamic therapy/sonodynamic therapy had an enhanced therapeutic effect. Moreover, the responsive degradable characteristic of PDA–MnO2-IR780 in the tumor microenvironment ensured excellent biological safety. These results reveal a great potential of PDA–MnO2-IR780 for safe and highly-efficiency synergistic therapy for cancer.

Lung cancer is the second most common tumor and has the highest mortality rate. Both novel therapeutic targets and approaches are needed to improve the overall survival of patients with lung cancer. MicroRNA-320a-3p belongs to the miR-320a family and has been reported as a tumor suppressor in multiple cancers. However, its definitive role and precise mechanism in the progression of lung cancer remain unclear. In this study, we developed a new type of gold nanorod modified with polyethyleneimine that targets cancer-specific nanoparticles by RGD peptide, which could condense miRNA to self-assemble supramolecular nanoparticles. The designed nanoparticles can achieve integrin αvβ3-targeted cancer therapy, realize photosensitive therapy by laser irradiation and attain gene-targeted therapy by miRNAs. These nanoparticles could deliver miR-320a into lung cancer cells specifically and efficiently. Moreover, we demonstrated that Au-RGD-miR-320a nanoparticles combined with laser irradiation dramatically inhibited the proliferation and metastasis, and enhanced the apoptosis of lung cancer, both in vitro and in vivo. In terms of the mechanism, miR-320a inhibits Sp1 expression by directly binding to the 3'UTR of Sp1, and it eventually enhanced the expression of PTEN and inhibited the expression of matrix metallopeptidase 9 (MMP9). These findings provide a new and promising anticancer strategy via the use of Au-RGD-miR-320a nanoparticles, and identify miR-320a/Sp1 as a potential target for future systemic therapy against lung cancer.

Photodynamic therapy (PDT) has been regarded as a promising strategy for tumor therapy. However, heterogeneous tumor microenvironments severely limit the efficacy of photodynamic therapy. In this work, a multifunctional theranostic platform (MnO2-SiO2-APTES&Ce6 (MSA&C)) was fabricated based on MnO2 nanoflowers, which afforded MRI-guided synergistic therapy incorporating PDT and second near-infrared window (NIR-II) photothermal therapy (PTT). Herein, MnO2 nanoflowers are first proposed as a NIR-II photothermal agent. In the MSA&C system, MnO2 nanoflowers were employed for effective photosensitizer loading, relieving tumor hypoxia, and NIR-II PTT and tumor-specific imaging. The large amount of photosensitizer, reduced tumor hypoxia, and hyperthermia all contributed to the improvement of PDT. The quantity of reactive oxygen species (ROS) generated during PDT in turn down-regulated the expression of heat shock proteins (HSP 70), thereby improving photothermal performance. Positively charged (3-aminopropyl)triethoxysilane (APTES) was used to promote cellular uptake, further improving treatment efficiency. In this system, the MSA&C nanoflowers can not only alleviate tumor hypoxia, but they also obviously induce cell apoptosis under laser irradiation through a ROS- and hyperthermia-mediated mechanism, thereby leading to remarkable tumor growth inhibition. Furthermore, the Mn2+ ions generated during treatment can be explored for MR imaging, and this could be used to finally realize MRI-guided enhanced PDT/PTT.

The construction of high-efficiency tumor theranostic platform will be of great interest in the treatment of cancer patients; however, significant challenges are associated with developing such a platform. In this study, we developed high-efficiency nanotheranostic agent based on ferroferric oxide, manganese dioxide, hyaluronic acid and doxorubicin (FMDH-D NPs) for dual targeting and imaging guided synergetic photothermal-enhanced chemodynamic/chemotherapy for cancer, which improved the specific uptake of drugs at tumor site by the dual action of CD44 ligand hyaluronic acid and magnetic nanoparticles guided by magnetic force. Under the acidic microenvironment of cancer cells, FMDH-D could be decomposed into Mn

Endometrial cancer (EC) is a common form of cancer in women. Metastasis is the main cause of EC treatment failure. Eukaryotic translation initiation factor 4E (eIF4E) is an oncogene that is overexpressed in a variety of malignancies and their distant metastases. The present study analyzed microarray data from the Oncomine database and revealed that high eIF4E expression was associated with poor prognosis and high pathological grade of EC. The expression of eIF4E was higher in EC tissues compared with in adjacent normal tissues. In addition, microRNA (miR)‑320a and miR‑340‑5p expression levels were downregulated in EC tissues compared with those in adjacent normal tissues, which suggested that these microRNAs may serve as EC tumor suppressor genes. miR‑320a and miR‑340‑5p could bind to the 3'‑UTR of eIF4E mRNA, thus downregulating the expression of eIF4E and phosphorylated (p)‑eIF4E in EC cells. Overexpression of miR‑320a or miR‑340‑5p effectively suppressed HEC‑1A cell migration and invasion. The downregulation of eIF4E and p‑eIF4E following miR‑320a or miR‑340‑5p transfection reduced the invasiveness and metastatic capability of EC cells in a manner associated with decreased expression of matrix metallopeptidase (MMP)‑3 and MMP‑9. In addition, one of the effects of transforming growth factor β1 (TGF‑β1), which is to induce the phosphorylation of eIF4E, was suppressed by miR‑320a and miR‑340‑5p overexpression. These two microRNAs also attenuated the features of TGF‑β1‑induced epithelial‑mesenchymal transition (EMT). In conclusion, the results of the present study demonstrated that eIF4E was upregulated in EC, whereas miR‑320a and miR‑340‑5p were downregulated in EC compared with adjacent normal tissues. In vitro, miR‑320a and miR‑340‑5p inhibited the migratory capability of EC cells by downregulating MMP‑3 and MMP‑9 and prevented TGF‑β1‑induced EMT through p‑eIF4E.

Objectives: To investigate epidemiological features and trends of influenza incidence with 1,173,640 cases in mainland China from 2005 to 2015. Methods: Incidence and mortality data for influenza from 2005 to 2015 were provided by the data-center of China public health science and covered a population of about 1.3 billion people from 31 provinces and regions in mainland China. Joinpoint regression and exploratory spatial data analyses were used to examine the incidence trends from 2005 to 2015. Results: The first upsurge in influenza cases occurred in 2009, and the highest incidence of influenza occurred in 2014 (15.9045 cases/100,000 people). The average incidence per year from 2009 to 2015 was threefold higher than that from 2005 to 2008 (10.5308 vs 3.4589 cases/100,000 people; incidence rate ratio = 3.0446). The joinpoint regression results showed that there was an increasing influenza incidence trend from 2005 to 2015 (annual change in percentage = 13.6%, 95%CI 2.2–26.3, p = 0.0236). The seasonal pattern analysis showed that influenza typically occurred in winter and spring during each monitoring year, peaking from November to March the next year. Conclusions: This study will help governments to make valuable decisions in allocating scarce resources and providing strategies to limit the spread of influenza. Keywords: Influenza, Epidemiology, Mainland China, Incidence, Seasonal pattern

RFWD2, an E3 ubiquitin ligase, is overexpressed in numerous human cancers, including leukemia, lung cancer, breast cancer, renal cell carcinoma, and colorectal cancer. The roles of RFWD2 in cancer are related to the targeting of its substrates for ubiquitination and degradation. This study aimed to investigate the role of TRIB2 in relation to the regulation of protein degradation through RFWD2. inBio Discover™ results demonstrated that TRIB2 can perform its functions by interacting with RFWD2 or other factors. TRIB2 can interact with and regulate RFWD2, which further attends the proteasome-mediated degradation of the RFWD2 substrate p-IκB-α. TRIB2 colocalizes with RFWD2-related IκB-α to form a ternary complex and further affects the IκB-α degradation by regulating its phosphorylation. Specific domain analysis showed that TRIB2 may bind to RFWD2 via its C-terminus, whereas it binds to IκB via its pseudokinase domain. TRIB2 acts as an oncogene and promotes cancer cell proliferation and migration, whereas RFWD2 knockdown reversed the role of TRIB2 in promoting cancer cell growth and colony formation in vitro and in vivo. In summary, this study reveals that TRIB2 promotes the progression of cancer by affecting the proteasome-mediated degradation of proteins through the interaction with RFWD2.

Lung cancer is one of the most common types of cancer, with the highest mortality rate worldwide. MicroRNAs play notable roles in the chemotherapeutic effects of anticancer drugs. The present study used reverse transcription-quantitative PCR, western blotting and cell migration and invasion assays to reveal the role of let-7f-1-3p in non-small cell lung cancer (NSCLC) and explore the effect of let-7f-1-3p on doxorubicin (DOX) treatment. It was demonstrated that the levels of let-7f-1-3p in carcinoma tissues were lower compared with those in paracarcinoma tissues. Thus, let-7f-1-3p may act as a suppressor gene. The present study also explored the role of let-7f-1-3p in A549 and NCI-H1975 cells. Results revealed that let-7f-1-3p could inhibit the viability, migration and invasion of NSCLC cells and induce their apoptosis. Integrin β1 acted as a target gene regulated by let-7f-1-3p. This suggested that let-7f-1-3p could enhance DOX-inhibited cell viability, migration and invasion in vitro. Overall, the present study demonstrated that let-7f-1-3p may act as a target for drug design and lung cancer therapy.

Background:Regenerating islet-derived gene family member 4 (Reg4), a well-investigated growth factor in the regenerative pancreas, has recently been reported to be highly associated with a majority of gastrointestinal cancers. Pathological hyper-expression or artificial over-expression of Reg4 causes acceleration of tumor growth, migration, and resistance to chemotherapeutic 5-Fluorouracil (5-FU). Until now, no method has been successfully established for eliminating the effects of Reg4 protein.Methods:This study reports the production of an engineered immunoglobin, a single-chain variable fragment (scFv-Reg4), to specifically bind Reg4 and block the bioactivity. The complementary-determining regions (CDRs) against Reg4 were assigned using MOE and ZDOCK servers. The binding affinity (KD) was determined by bio-layer interferometry (BLI). MKN45 and AGS cell proliferation was determined by Thiazolyl blue tetrazolium bromide (MTT) method and the cell apoptosis was detected by flow cytometry assay.Results:The KD of scFv-Reg4 to Reg4 was determined to be 1.91×10-8. In MKN45 and AGS cell lines, scFv- Reg4 depressed Reg4-stimulated cell proliferation and the inhibitory rates were 27.7±1.5% and 17.3±2.6%, respectively. Furthermore, scFv significantly enhanced 5-FU-induced cell death, from 23.0±1.0% to 28.4±1.2% in MKN45 and 28.2±0.7% to 36.6±0.6% in AGS cells. Treatment with scFv alone could lyse cancer cells to a certain extent, but no significance has been observed.Conclusion:The single-chain antibody (scFv-Reg4) significantly inhibited gastric cancer cell proliferation and synergistically enhanced the lethal effect of 5-FU. Thus, traditional chemo-/radio- therapeutics supplemented with scFv-Reg4 may provide advances in the strategy for gastrointestinal cancer treatment.

Previous studies have confirmed that protein tyrosine phosphatase 1B (PTP1B) can promote tumour progression in non-small cell lung cancer (NSCLC). Vanadyl alginate oligosaccharides (VAOS) is a new coordination compounds that possesses a good PTP1B inhibitory activity. However, the potent anticancer efficacy of VAOS in human NSCLC requires further study. In this study, VAOS exhibited effective inhibitory effects in NSCLC both in cultured cells and in a xenograft mouse model. VAOS was further identified to induce NSCLC cell apoptosis through activating protein kinase B (AKT) to elevate intracellular reactive oxygen species (ROS) levels by increasing in oxygen consumption and impairing the ROS-scavenging system. Neither silencing of PTP1B by siRNA nor transient overexpression of PTP1B had an effect on the AKT phosphorylation triggered by VAOS, indicating that PTP1B inhibition was not involved in VAOS-induced apoptosis. Through phosphorus colorimetric assay, we demonstrated that VAOS notably inhibited phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylation activity, another member of the protein tyrosine phosphatases (PTPases)-upstream factor of AKT. Interestingly, PTEN knockdown sensitized cells to VAOS, whereas ectopic expression of PTEN markedly rescued VAOS-mediated lethality. In vivo, VAOS treatment markedly reduced PTEN activity and tumour cell burden with low systemic toxicity. Thus, our data not only provided a new therapeutic drug candidate for NSCLC, but presented new understanding into the pharmacological research of VAOS.

The emergence of multidrug resistance (MDR) in malignant tumors is the primary reason for invalid chemotherapy. Antitumor drugs are often adversely affected by the MDR of tumor cells. Treatments using conventional drugs, which have specific drug targets, hardly regulate the complex signaling pathway of MDR cells because of the complex formation mechanism of MDR. However, natural products have positive advantages, such as high efficiency, low toxicity, and ability to target multiple mechanism pathways associated with MDR. Natural products, as MDR reversal agents, synergize with chemotherapeutics and enhance the sensitivity of tumor cells to chemotherapeutics, and the co-delivery of natural products and antitumor drugs with nanocarriers maximizes the synergistic effects against MDR in tumor cells. This review summarizes the molecular mechanisms of MDR, the advantages of natural products combined with chemotherapeutics in offsetting complicated MDR mechanisms, and the types and mechanisms of natural products that are potential MDR reversal modulators. Meanwhile, aiming at the low bioavailability of cocktail combined natural products and chemotherapeutic in vivo, the advantages of nanoplatform-based co-delivery system and recent research developments are illustrated on the basis of our previous research. Finally, prospective horizons are analyzed, which are expected to considerably improve the nano-co-delivery of natural products and chemotherapeutic systems for MDR reversal in cancer.

Non-coding RNAs (ncRNAs) involve in diverse biological processes by post-transcriptional regulation of gene expression. Emerging evidence shows that miRNA-4293 plays a significant role in the development of non-small cell lung cancer. However, the oncogenic functions of miR-4293 have not been studied. Our results demonstrated that miR-4293 expression is markedly enhanced in lung carcinoma tissue and cells. Moreover, miR-4293 promotes tumor cell proliferation and metastasis but suppresses apoptosis. Mechanistic investigations identified mRNA-decapping enzyme 2 (DCP2) as a target of miR-4293 and its expression is suppressed by miR-4293. DCP2 can directly or indirectly bind to WFDC21P and downregulates its expression. Consequently, miR-4293 can further promote WFDC21P expression by regulating DCP2. With a positive correlation to miR-4293 expression, WFDC21P also plays an oncogenic role in lung carcinoma. Furthermore, knockdown of WFDC21P results in functional attenuation of miR-4293 on tumor promotion. In vivo xenograft growth is also promoted by both miR-4293 and WFDC21P. Overall, our results establish oncogenic roles for both miR-4293 and WFDC21P and demonstrate that interactions between miRNAs and lncRNAs through DCP2 are important in the regulation of carcinoma pathogenesis. These results provided a valuable theoretical basis for the discovery of lung carcinoma therapeutic targets and diagnostic markers based on miR-4293 and WFDC21P.

Peritrophic membrane (PM) refers to a vital physical barrier enabling shrimp to resist pathogen invasion. It primarily consists of chitin and proteins, mostly chitin-binding protein (CBP). CBPs have been identified from microorganisms to higher organisms. In the present study, a CBP, designated MjCBP, was reported from Marsupenaeus japonicus. The open reading frame of MjCBP was 1854 bp, encoding a protein with 618 amino acids (MH544098). To be specific, the theoretical pI and molecular mass of mature MjCBP reached 5.43 and 66064.00 Da, respectively. MjCBP consisted of seven type Ⅱ chitin-binding domains (ChtB D2), which was up-regulated after being challenged with Vibrio anguillarum and then agglutinating several bacteria. In addition, MjCBP and the first chitin-binding domain (CBD1) could bind to several Gram-positive and Gram-negative bacteria via the binding process to lipopolysaccharides and peptidoglycans, whereas CBD1 was not capable of agglutinating bacteria. Moreover, the anterior and posterior segments of CBD1 were synthesized in vitro, and the posterior segment could bind to lipopolysaccharides. However, both segments fail to agglutinate bacteria. Furthermore, MjCBP and CBD1 facilitated the clearance of V. anguillarum in vivo, and the silencing of MjCBP via RNA interference reduced the ability of bacterial clearance. As revealed from the mentioned results, MjCBP acts as an opsonin or pattern recognition receptor to achieve antibacterial immune response in shrimp.

Chronic myeloid leukemia (CML) is a malignant hematological disease, and drug resistance is often related to poor prognosis. MicroRNAs (miRNA) play a pivotal role in transcriptional regulation, cell development, and chemotherapy resistance. Here, we describe the effect of let-7b on resistant leukemia cells and examine the relevance of let-7b as a biomarker for adriamycin resistance. Results showed that let-7b was downregulated in K562/ADM (KA) cells, and the downregulation of let-7b in K562 and KA cells increased ADM resistance. The inhibition of let-7b subsequently induced the upregulation of AURKB. Finally, results proved that the Pi3k/Akt/Erk pathway was related to AURKB-activated resistance. Our research indicated that the underexpression of let-7b and overexpression of AURKB contributed to the resistance of CML, and its function is partly regulated by the Pi3k/Akt/Erk pathway. Thus, our further understand of its inhibitory effect may promise a new therapeutic strategy to overcome chemotherapeutic resistance in CML.

Background: Emerging evidence shows that lncRNA WFDC21P could promote STAT3 phosphorylation and microRNA 4293 SNP is associated with the risk of carcinomas, but the oncogenic functions of WFDC21P and miR-4293 in lung carcinoma are unclear.Methods: mRNA sequencing of lung carcinoma and control para-carcinoma tissues was performed to screen the potential targets. WFDC21P and miR-4293 levels were evaluated in lung carcinoma cells and tissues by qRT-PCR. The function of WFDC21P and miR-4293 on proliferation, apoptosis and metastasis were assessed by MTT, FACS, western blot, transwell assays, colony formation assays and xenografts experiment. RNA immunoprecipitation assays were implemented to verify the relationship between WFDC21P and mRNA-decapping enzyme 2 (DCP2). Furthermore, gain/loss of miR-4293 functions were used to determine its targeting relationship of DCP2. Results: WFDC21P expression is markedly enhanced in lung carcinoma tissue and cells. Moreover, WFDC21P promotes tumor cell proliferation and metastasis but suppresses apoptosis. Mechanistic investigations identified DCP2 can directly bind to WFDC21P and down-regulates its expression. DCP2 as a direct target of miR-4293 and its expression is suppressed by miR-4293. Consequently, miR-4293 can further promote WFDC21P expression by regulating DCP2. With positive correlation to WFDC21P expression, miR-4293 also plays oncogenic role in lung carcinoma. Furthermore, knockdown of WFDC21P results in functional attenuation of miR-4293 on tumor promotion. In vivo xenograft growth is also promoted by both WFDC21P and miR-4293. Conclusion: Our results establish oncogenic roles for both WFDC21P and miR-4293, and demonstrate that interactions between miRNAs and lncRNAs through DCP2 are important in lung carcinoma pathogenesis.

Background Long noncoding (lncRNA) single‐nucleotide polymorphisms (SNPs) are associated with the susceptibility to the development of various malignant tumors. The aim of this study was to investigate the roles of HOX transcript antisense intergenic RNA (HOTAIR) and its SNPs in lung cancer. Methods Initially, the expression of HOTAIR in different tumors was investigated using the online Gene Expression Profiling Interactive Analysis (GEPIA) resource. Three SNPs (rs920778, rs1899663, and rs4759314) of HOTAIR were identified using the MassArray system. Following this, the relationship between these SNPs and susceptibility to lung cancer was investigated. Results Expression of HOTAIR was found to increase in a variety of cancers, including nonsmall cell lung cancer (NSCLC). We found that the genotypes of these SNPs (rs920778, rs1899663, and rs4759314) were not significantly associated with lung cancer type, family history, lymph node metastasis, or lung cancer stage. In gender stratification, the results of rs920778 genotypes showed that, compared to genotype AA, the AG (OR = 0.344, 95% CI: 0.133–0.893, p = .028) and AG + GG (OR = 0.378, 95% CI: 0.153–0.932, p = .035) genotypes of rs920778 are protective factors against NSCLC in females. In smoking stratification, compared with AA of rs920778, the genotype AG + GG (OR = 0.507, 95% CI: 0.263–0.975, p = .042) was a protective factor against NSCLC in nonsmoking people. No statistical differences were observed in the classifications of rs1899663 and rs4759314 genotypes. Linkage disequilibrium analysis revealed a high linkage disequilibrium between the rs920778 and rs1899663 (D′ = 0.99, r 2 = .74), rs920778 and rs4759314 (D′ = 0.85, r 2 = .13), and rs1899663 and rs4759314 (D′ = 0.79, r 2 = .00). Conclusion Our study demonstrated that HOTAIR expression increased in NSCLC, and that the genotypes of rs920778 could be useful in the diagnosis and prognosis of lung cancer., This study investigated the roles of HOTAIR and its SNPs in lung cancer. We found that HOTAIR increased in nonsmall cell lung cancer, and the genotypes of rs920778 are protective factors for female patients and nonsmoking people, which are useful for screening and prognosis for lung cancer.

Several studies have demonstrated that cancer radiosensitivity is associated with the deregulation of c‑Myc, but the relationship between c‑Myc and Fas in radioresistance of lung adenocarcinoma remains unclear. In this study, we established radiation-resistant A549 cell model (A549/R), and investigated the roles of c‑Myc and Fas in radiation-induced cytotoxicity of A549 cells. Apoptosis detection showed that there were fewer apoptotic cells in A549/R cells treated with radiation than in A549 cells. Western blotting results demonstrated the inverse expression pattern of c‑Myc and Fas in A549 and A549/R cells. Suppression of c‑Myc expression by small interfering RNA (siRNA) displayed enhancement of Fas-mediated apoptosis in A549/R cells, accompanying a significant decrease of Bid, Bcl‑2, pro‑caspase‑8, -9 and -3 and increase of Bax. In contrast, Fas-mediated apoptosis was attenuated while Fas expression was suppressed by ectopic expression of c‑Myc in A549 cells. Moreover, decreased cell viability and increased induction of apoptosis were observed in A549/R cells followed by combinational treatment of c‑Myc siRNA and irradiation, whereas, upregulation of c‑Myc reduced the sensitivity of A549 cells to irradiation. These results indicated that c‑Myc and Fas regulated the sensitivity of A549 cells to irradiation by regulating caspase‑8-mediated Bid activation and the subsequent association with the mitochondrial pathway of apoptosis.

Chemotherapy is the main treatment method for patients with chronic myeloid leukemia (CML) and has achieved marked results. However, the acquisition of multidrug resistance (MDR) has seriously affected the quality of life and survival rate of patients. The overexpression of the inhibitors of apoptosis proteins (IAPs) and the adenosine triphosphate (ATP)-dependent binding cassette (ABC) transporters are the two main causes of MDR. Apollon and MDR1 are the most important and representative members, respectively, among the IAPs and ABC transporters. In the present study, we investigated the role of Apollon and MDR1 in chemotherapy resistance and their mechanism of interaction. We respectively knocked down the expression of Apollon and MDR1 using short hairpin RNA (shRNA) in adriamycin (ADM) resistant human CML K562 cells and examined the drug sensitivity, the consequences with regard to ADM accumulation and the alterations in the expression of Apollon and MDR1. The expression levels of Apollon and MDR1 mRNA were higher in the K562/ADM cells compared with the parental K562 cells as determined by reverse transcription‑polymerase chain reaction (RT-PCR). The plasmids of Apollon and MDR1 shRNA were respectively stably transfected into K562/ADM cells using Lipofectamine 2000. The transfection efficiency was detected by fluorescence microscopy. Cell Counting Kit-8 (CCK-8) assay revealed that Apollon or MDR1 knockdown significantly increased the chemosensitivity of the K562/ADM cells to ADM. Flow cytometric assay revealed that K562/ADM/shMDR1 cells exhibited a significantly increased intracellular accumulation of ADM, and that changes were not found in the K562/ADM/shApollon cells. Compared with the parental K562/ADM cells, a significantly decreased expression of Apollon mRNA and protein was determined in the K562/ADM/shApollon cells without affecting the expression of MDR1 as determined by RT-PCR and western blotting. Likewise, the expression levels of MDR1 mRNA and protein also markedly downregulated in the K562/ADM/shMDR1 cells had no effect on Apollon expression. Collectively, our findings demonstrated, for the first time, that downregulation of Apollon or MDR1 through stable transfection with the Apollon- or MDR1-targeting shRNA induced MDR reversal through respective inhibition of Apollon or MDR1 expression and function. However, the reversal mechanism of Apollon and MDR1 revealed no direct interaction with each other.

Nuciferine, a major aporphine alkaloid constituent of lotus leaves, is a raw material for obesity treatment. Extensive studies have revealed that obesity is associated with pancreatic cancer (PC). However, it has not been clarified whether nuciferine could be used in PC treatment or prevention. Here, we show that nuciferine could enhance the sensitivity of PC cells to gemcitabine in both cultured cells and the xenograft mouse model. The mechanism study demonstrated that nuciferine induced YAP Ser127 phosphorylation [pYAP(Ser127)] through AMPK-mediated 3-hydroxy-3-methyl-glutaryl-coA reductase (HMGCR) downregulation. Remarkably, wild-type YAP overexpression or YAP Ser127 mutant could resist to nuciferine and no longer sensitize PC cells to gemcitabine. Knockdown of AMPK attenuated pYAP(Ser127) induced by nuciferine. Moreover, knockdown of AMPK reversed nuciferine-mediated HMGCR downregulation. Notably, HMGCR inhibiting could restrain YAP by phosphorylation Ser 127, and therefore enhance the efficiency of gemcitabine in PC cells. In line with this consistent, overexpression of HMGCR reduced growth inhibition caused by nuciferine and/or gemcitabine treatment in PC cells. In summary, these results provide an effective supplementary agent and suggest a therapeutic strategy to reduce gemcitabine resistance in PC.

MicroRNAs (miRNAs/miRs) serve important roles in the chemotherapeutic effect of anticancer drugs. To investigate the roles of miRNAs in cisplatin‑induced suppression of lung adenocarcinoma cell proliferation, A549 cells were treated with different concentrations of cisplatin. An MTT assay demonstrated that cisplatin inhibited A549 cell proliferation in a dose‑dependent manner. Cisplatin induced cell apoptosis and inhibited cell migration by increasing the levels of miR‑93, miR‑26a and miR‑26b. Furthermore, as an upstream factor, miR‑93 was proposed to regulate cyclin D2 expression in miR‑93‑transfected A549 cells. Cisplatin also induced Bcl‑2‑associated X protein expression, and decreased that of Bcl‑2 and c‑Myc in lung adenocarcinoma cells. In vivo analysis further supported that cisplatin inhibited lung adenocarcinoma cell growth by regulating cyclin D2 and miR‑93 expression. In conclusion, our findings demonstrated that cisplatin could effectively inhibit lung adenocarcinoma cell proliferation by decreasing cyclin D2 expression via miR‑93.

L-type lectins (LTLs) belong to the lectin family and are characterized by a conserved structural motif in their carbohydrate recognition domain. LTLs are homologous to leguminous lectins. In this study, we identified and functionally characterized an LTL from kuruma shrimp Marsupenaeus japonicus. We designated this LTL as MjLTL2. MjLTL2 contains a signal peptide, a Lectin_leg domain, a coiled coil, and transmembrane domain. MjLTL2 is distributed in hemocytes, heart, hepatopancreas, gill, stomach, and intestine; higher expression levels are seen in hemocytes and the hepatopancreas than in other tissues. MjLTL2 was upregulated following challenge of shrimp with Vibrio anguillarum and white spot syndrome virus (WSSV). MjLTL2 can agglutinate several bacteria without Ca2+. In addition, MjLTL2 could bind to several Gram-positive and -negative bacteria by binding to their lipopolysaccharide and peptidoglycan. However, MjLTL2 could not enhance the clearance of V. anguillarum in vivo. In the presence of WSSV infection, MjLTL2 knockdown by RNA interference resulted in a 7-day lower cumulative mortality of M. japonicus. Moreover, less VP19, VP24, VP26, and VP28 mRNAs were extracted from the hemocytes of MjLTL2 knockdown shrimp than from the control. These results suggest that MjLTL2 is involved in immune responses in shrimp., Highlights • MjLTL2 could agglutinate several Gram-positive and -negative bacteria. • MjLTL2 could bind to several Gram-positive and -negative bacteria. • MjLTL2 could bind to lipopolysaccharide and peptidoglycan. • MjLTL2 knockdown resulted in a lower cumulative mortality of M. japonicus in the presence of WSSV infection. • MjLTL2 knockdown resulted in a lower VP19, VP24, VP26, and VP28 expression levels.

In treating eye diseases, topical administration on the ocular surface is the most convenient and acceptable route. However, the intraocular efficiency of non-invasive drug delivery systems is still considerably hampered by the eye's defense barriers. In this work, cell-penetrating peptide TAT-functionalized, flurbiprofen-loaded liposomes (TAT-FB-Lip) were designed to enable transcorneal drug delivery and prolong ocular surface retention. The corneal penetration-promoting properties of TAT-functionalized liposomes (TAT-Lip) were confirmed in vitro using a corneal permeability assay and the HCE-T cell sphere model and in vivo by aqueous humor pharmacokinetics assessment. TAT-Lip induced an increase in intracellular calcium ion concentration and membrane potential depolarization. F-actin images of HCE-T cells treated with TAT-Lip show the tight junctions between cells partly opened. The cellular internalization pathway mainly depended on the electrostatic interaction between TAT-Lip and the cell membrane, and there is a certain degree of energy dependence. The pharmacokinetics of flurbiprofen in tears demonstrated TAT-Lip could reduce the drug loss rate. Moreover, the anti-inflammatory effect of TAT-FB-Lip was enhanced by markedly suppressing PGE2, IL-6, and TNF-α production in tears and aqueous humor in a rabbit conjunctivitis model. In conclusion, this work demonstrates that TAT-Lip is an effective ocular drug carrier system that facilitates transcorneal delivery.

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) has been reported to play a pivotal role in tumor chemotherapy failure. Study after study has illustrated that the phosphoinositide 3-kinase (PI3K)/Akt signaling cascade is involved in the MDR phenotype and is correlated with P-gp expression in many human malignancies. In the present study, osthole, an O-methylated coumarin, exhibited potent reversal capability of MDR in myelogenous leukemia K562/ADM cells. Simultaneously, the uptake and efflux of Rhodamine-123 (Rh-123) and the accumulation of doxorubicin assays combined with flow cytometric analysis suggested that osthole could increase intracellular drug accumulation. Furthermore, osthole decreased the expression of multidrug resistance gene 1 (MDR1) at both the mRNA and protein levels. Further experiments elucidated that osthole could suppress P-gp expression by inhibiting the PI3K/Akt signaling pathway which might be the main mechanism accounting for the reversal potential of osthole in the MDR in K562/ADM cells. In conclusion, osthole combats MDR and could be a promising candidate for the development of novel MDR reversal modulators.

Multidrug resistance (MDR) of leukemia cells is a major obstacle in chemotherapeutic treatment. The high expression and constitutive activation of P-glycoprotein (P-gp) and multidrug resistance protein-1 (MRP-1) have been reported to play a vital role in enhancing cell resistance to anticancer drugs in many tumors. The present study aimed to investigate the reversal of MDR by silencing homeobox A10 (HOXA10) in adriamycin (ADR)-resistant human chronic myelogenous leukemia (CML) K562/ADM cells by modulating the expression of P-gp and MRP-1. K562/ADM cells were stably transfected with HOXA10-targeted short hairpin RNA (shRNA). The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis showed that the mRNA and protein expression of HOXA10 was markedly suppressed following transfection with a shRNA-containing vector. The sensitivity of the K562/ADM cells to ADR was enhanced by the silencing of HOXA10, due to the increased intracellular accumulation of ADR. The accumulation of ADR induced by the silencing of HOXA10 may be due to the downregulation of P-gp and MRP-1. Western blot analysis revealed that downregulating HOXA10 inhibited the protein expression of P-gp and MRP-1. Taken together, these results suggest that knockdown of HOXA10 combats resistance and that HOXA10 is a potential target for resistant human CML.

One of the major causes of failure in chemotherapy for patients with human chronic myelogenous leukemia (CML) is the acquisition of multidrug resistance (MDR). MDR is often associated with the overexpression of drug efflux transporters of the ATP-binding cassette (ABC) protein family. Timosaponin A-III (TAIII), a saponin isolated from the rhizome of Anemarrhena asphodeloides, has previously demonstrated the ability to suppress certain human tumor processes and the potential to be developed as an anticancer agent. Nevertheless, the ability of TAIII to reverse MDR has not yet been explored. In this study, the adriamycin (ADM) resistance reversal effect of TAIII in human CML K562/ADM cells and the underlying mechanism was investigated. The Cell Counting Kit-8 (CCK-8) assay showed that TAIII had a reversal effect on the drug resistance of K562/ADM cells. Flow cytometry assay showed increased intracellular accumulation of ADM after cells were pretreated with TAIII, and the changes in the accumulation of rhodamine-123 (Rho-123) and 5(6)-carboxyfluorescein diacetate (CFDA) dye in K562/ADM cells were determined to be similar to the changes of intracellular accumulation of ADM. After pretreatment of cells with TAIII, the decreasing expression of P-gp and MRP1 mRNA was examined by reverse transcription polymerase chain reaction (RT-PCR). Western blotting showed TAIII inhibiting P-gp and MRP1 expression depended on the PI3K/Akt signaling pathway by decreasing the activity of p-Akt. Moreover, wortmannin an inhibitor of PI3K/Akt signaling pathway has a strong inhibitory effect on the expression of p-Akt, P-gp and MRP1. Besides, the combined treatment with TAIII did not have an affect on wortmannin downregulation of p-Akt, P-gp and MRP1. Taken together, our findings demonstrate, for the first time, that TAIII induced MDR reversal through inhibition of P-gp and MRP1 expression and function with regained adriamycin sensitivity which might mainly correlate to the regulation of PI3K/Akt signaling pathway.

Multidrug resistance (MDR) in leukemia cells is a major obstacle to chemotherapeutic treatment. High expression and constitutive activation of multidrug resistance protein 1 (MRP1) has been associated with the development of resistance to anticancer drugs in a number of tumor types. The activity of c-Jun N-terminal kinase 1 (JNK1) is associated with the occurrence of MDR and MRP1 expression. The present study aimed to investigate the ability of solanine to resensitize the Adriamycin® (ADR)-resistant human myelogenous leukemia cell line K562/ADM to ADR. Results of the Cell Counting Kit-8 assay demonstrated that solanine inhibited K562/ADM cell proliferation. K562/ADM cell sensitivity to ADR was increased following treatment with solanine, indicated by increased intracellular accumulation of ADR. Western blotting demonstrated that treatment with solanine led to reduced MRP1 protein expression, suggesting that solanine-induced ADR accumulation is due to the downregulation of MRP1 expression. Solanine-mediated MRP1 downregulation was observed to be dependent on the JNK signaling pathway. In conclusion, the results of the present study suggest that solanine reverses MDR in K562/ADM cells and may represent a novel therapeutic agent for the treatment of human myelogenous leukemia.

Solanine is an alkaloid and is the main extract of the traditional Chinese herb, Solanum nigrum Linn. It has been reported that Solanine has anti-inflammatory and antitumor properties. The present study aimed to investigate the antitumor effect of Solanine in Jurkat cells and demonstrate the molecular mechanism of antitumor activity of Solanine. A Cell Counting Kit-8 assay demonstrated that Solanine inhibited the proliferation of Jurkat cells in a dose-and time-dependent manner. Cell apoptosis was measured by flow cytometry. Flow cytometry revealed that Solanine induced apoptosis in a dose-dependent manner in Jurkat cells. Reverse transcription-quantitative polymerase chain reaction demonstrated that Solanine modulated the mRNA levels of B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Additionally, Bcl-2 and Bax expression was measured using western blot analysis. Western blot analysis revealed a significant increase in the expression of Bax and decrease in the expression of Bcl-2. Solanine increased the chemosensitivity of Jurkat cells to Adriamycin. In summary, the present results indicated that the antitumor activity of Solanine was associated with inhibition of cell proliferation, induction of apoptosis and increasing cytotoxicity of Adriamycin. Therefore, Solanine may have potential as a novel agent for the treatment of acute lymphocytic leukemia.

MicroRNAs (miRNAs or miRs) have recently become a popular focus of cancer research due to their ability to act as oncogenes or tumor suppressors. In the present study, miR‑33a‑5p expression was identified to be downregulated in lung adenocarcinoma samples compared with normal, which suggested that miR‑33a‑5p may serve as a tumor suppressor gene. Transfection with miR‑33a‑5p mimics inhibited the proliferation and migration of A549 and LTEP‑a‑2 cells and increased cellular apoptosis. A luciferase reporter assay confirmed that miR‑33a‑5p targets the 3'‑untranslated region of the mechanistic target of rapamycin (mTOR) gene. mTOR expression was decreased in A549 and LTEP‑a‑2 cells treated with miR‑33a‑5p mimics, as well as the expression of its downstream effectors phosphorylated (p)‑p70 ribosomal protein S6 kinase (p70S6K) and p‑eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). Following treatment with celastrol, miR‑33a‑5p expression was upregulated, and miR‑33a‑5p could enhance cellular sensitivity to celastrol. Western blot analysis revealed that the expression of mTOR, p‑p70S6K and p‑4EBP1 decreased following celastrol treatment. These results suggested that mTOR was involved in the mechanism by which miR‑33a‑5p enhanced the sensitivity of lung adenocarcinoma cells to celastrol. Furthermore, LTEP‑a‑2 cells were xenografted subcutaneously into nude mice, to examine the effect of celastrol and miR‑33a‑5p on the growth of LTEP‑a‑2 cells in vivo. The results demonstrated that tumor growth in the celastrol‑treated or miR‑33a‑5p‑treated group was attenuated compared with the control group. Notably, tumor growth in the combination treatment group was almost arrested after 2 weeks. In addition, celastrol upregulated the expression of miR‑33a‑5p, and high expression of miR‑33a‑5p inhibited mTOR and its downstream effectors. In summary, miR‑33a‑5p inhibited the proliferation of lung adenocarcinoma cells, enhanced the antitumor effect of celastrol, and improved sensitivity to celastrol by targeting mTOR in lung adenocarcinoma in vitro and in vivo.

Cumulative evidence has indicated that celastrol may suppress cancer growth; however, the underlying mechanism requires further investigation. In the present study, A549 cells were treated with various concentrations of celastrol. Lung cancer cell proliferation was evaluated using an MTT assay and observed under a microscope. Cell apoptosis was detected by Annexin V fluorescein isothiocyanate/propidium iodide double-labeled flow cytometry. The results demonstrated that celastrol suppressed proliferation and induced apoptosis in a dose-independent manner. Celastrol may also decrease the phosphorylation levels of signal transducer and activator of transcription 3 (STAT3) and the B cell lymphoma-2 (Bcl-2)/Bcl-2 associated C protein (Bax) ratio. As microRNA (miR-24 and miR-181b) were predicated to target STAT3, STAT3 activation was inhibited in miR-24-or miR-181b-treated A549 cells compared with the control treatment. The ratio of Bcl-2/Bax was further reduced in miR-24 or miR-181b-treated A549 cells. The results were further confirmed by detecting in another lung adenocarcinoma cell line, LTEP-a-2. In summary, the results of the present study demonstrated that celastrol treatment suppressed the proliferation and induced apoptosis by regulating the expression levels of miR-24 and miR-181b.

Activating transcription factor 6 (ATF6) pathway is the key branch of unfolded protein response (UPR). In this study, a homolog of ATFα from Marsupenaeus japonicus (MjATF6) was identified using genome sequencing and characterized, so as to investigate the role of ATF6 pathway in anti-viral immunity of M. japonicus. The cDNA of MjATF6 obtained was 1008 bp in length, with an open reading frame (ORF) of 849bp, which had encoded a putative of 283 amino acid proteins. Results of qRT-PCR showed that MjATF6 was distributed in all the six tested tissues, with the higher expression level being seen in hemocytes and hepatopancreas. Furthermore, MjATF6 expression would be up-regulated from 1 day to 7 day under white spot syndrome virus (WSSV) challenge. In comparison, RNA interference-induced MjATF6 knockdown had resulted in a lower 7-day cumulative mortality of M. japonicus in the presence of WSSV infection. Additionally, our results also revealed that less VP28 mRNA was extracted from hemocytes or hepatopancreas of MjATF6 knockdown shrimp than that from the control. Taken together, these results have confirmed that ATF6 pathway is vital for WSSV replication, and that UPR in M. japonicus may facilitate WSSV infection.

This paper is aimed at proposing a mobile cloud computing system called M2C (Mobile Math Cloud). This system provides users with an APP to accelerate the execution of MATLAB instructions and scripts on their Android-based mobile devices by taking advantage of diverse processors including CPUs and GPUs available in clouds. On the other hand, it supports time-sharing license management to reduce the user time of waiting system services and increase the resource utilization of clouds. Moreover, it supports parallel computing and optimal resource configurations for maximizing the performance of user applications, and faulty tolerance for recovering the contexts of user programs from system faults. With these supports, M2C provides a reliable and efficient service for mobile users to perform massive mathematical computation anytime anywhere.

Pulmonary fibrosis (PF) is a disease with an unknown cause and a poor prognosis. In this study, we aimed to explore the pathogenesis of PF and the mechanism of sulindac in attenuating bleomycin (BLM)-induced PF. The rat PF model was induced by BLM and verified through histological studies and hydroxyproline assay. The severity of BLM-induced PF in rats and other effects, such as the extent of the wet lung to bw ratios, thickening of alveolar interval or collagen deposition, was obviously ameliorated in sulindac-treated rat lungs compared with BLM-induced lungs. Sulindac also reversed the epithelial mesenchymal transition (EMT) and inhibited the PF process by restoring the levels of E-cadherin and α-smooth muscle actin (SMA) in A549 cells. Our results further demonstrated that the above effects of sulindac might be related to regulating of interferon gamma (IFN-γ) expression, which further affects signal transducers and activators of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) levels. Moreover, higher miR-21 levels with the decreased E-cadherin and increased α-SMA expressions were found in transforming growth factor-β1-treated A549 cells, which can be reversed by sulindac. Collectively, our results demonstrate that by decreasing IFN-γ-induced STAT3/p-STAT3 expression to down-regulate miR-21, sulindac could significantly reverse EMT in A549 cells and prevent BLM-induced PF.

Circulating microRNAs (miRNAs) are important in the diagnosis of a number of diseases, since serum or plasma miRNAs are more stable compared with miRNA isolated from blood samples. The aim of the present study was to investigate the association between the expression levels of serum let-7c miRNA and the clinical diagnosis of breast cancer (BC). The circulating let-7c levels of 90 BC patients and 64 healthy controls were determined by performing a reverse transcription-quantitative polymerase chain reaction assay. The results demonstrated that let-7c expression was downregulated in the BC tissues compared with the paracarcinoma control tissues. In addition, the let-7c expression in the serum of BC patients was significantly lower compared with the healthy controls (P

Lung cancer is the most common cause of cancer-associated mortality. MicroRNAs (miRNAs), as oncogenes or tumor suppressor genes, serve crucial roles not only in tumorigenesis, but also in tumor invasion and metastasis. Although miRNA-let-7a (let-7a) has been reported to suppress cell growth in multiple cancer types, the biological mechanisms of let-7a in lung adenocarcinoma are yet to be fully elucidated. In the present study, the molecular roles of let-7a in lung adenocarcinoma were investigated by detecting its expression in lung adenocarcinoma tissues and exploring its roles in the regulation of lung cancer cell proliferation. Let-7a expression was identified to be downregulated in lung adenocarcinoma tissues compared with normal tissues. Overexpression of let-7a effectively suppressed cancer cell proliferation, migration and invasion in H1299 and A549 cells. Let-7a also induced cell apoptosis and cell cycle arrest. Furthermore, let-7a significantly inhibited cell growth by directly regulating cyclin D1 signals. This novel regulatory mechanism of let-7a in lung adenocarcinoma provides possible avenues for future targeted therapies of lung cancer.