Senolytic combination of dasatinib and quercetin attenuates renal damage in diabetic kidney disease.

BACKGROUND: Senolytic combination of dasatinib and quercetin (DQ) is the most studied senolytics drugs used to treat various age-related diseases. However, its protective activity against diabetic kidney disease (DKD) and underlying mechanisms are uncertain. PURPOSE: To investigate the functions and potential mechanisms of the senolytics DQ on DKD. METHODS: Diabetic db/db mice were administrated DQ or transfected with over-expressed PPARα or shPPARα vector. The positive control group was administered irbesartan. Renal function and fibrotic changes in kidney tissue were tested. Single-cell RNA-seq (scRNA-seq) was conducted to analyze the differential transcriptome between the diabetic and control mice. Molecular docking simulation was used to assess the combination of DQ and potential factors. Moreover, tubular epithelial cells under high-glucose (HG) conditions were incubated with DQ and transfected with or without over-expressed PPARα/siPPARα vector. RESULTS: DQ significantly improved renal function, histopathological and fibrotic changes, alleviated lipid deposition, and increased ATP levels in mice with DKD. DQ reduced multiple fatty acid oxidation (FAO) pathway-related proteins and up-regulated PPARα in db/db mice. Overexpression of PPARα upregulated the expression of PPARα-targeting downstream FAO pathway-related proteins, restored renal function, and inhibited renal fibrosis in vitro and in vivo. Moreover, molecular docking and dynamics simulation analyses indicated the nephroprotective effect of DQ via binding to PPARα. Knockdown of PPARα reversed the effect of DQ on the FAO pathway and impaired the protective effect of DQ during DKD. CONCLUSION: For the first time, DQ was found to exert a renal protective effect by binding to PPARα and attenuating renal damage through the promotion of FAO in DKD.

Artificial aging conditions for Artemisia argyi leaves based on quality-inflammation-quality marker transformation.

BACKGROUND: Appropriate conditions for storage of Artemisia argyi leaves reduce irritation during treatment and increase the active ingredient content. Naturally aged A. argyi leaves (≥1 year) are optimal for moxibustion; however, this process is time-consuming and costly. A comprehensive understanding of the conditions for artificial aging of A. argyi leaves and the mechanism of quality-marker conversion are required to guarantee A. argyi quality and moxibustion efficacy. OBJECTIVE: To identify the optimal conditions for artificial aging of A. argyi leaves and clarify the mechanism of quality-marker conversion. METHOD: Gas chromatography (GC), high-performance liquid chromatography (HPLC), colorimeter (CD), and near-infrared spectroscopy (NIRS) were used to determine the chemical composition of A. argyi leaves before and after artificial and natural (1 year) aging and to determine the optimal artificial aging conditions. The effects of both artificially and naturally aged A. argyi leaves were then evaluated in a mouse model of ulcerative colitis (UC). The main chemical components of aged A. argyi leaves were then analyzed to determine quality-markers and the transformation mechanism. RESULTS: Comprehensive analysis of volatile and non-volatile components, color values, and characteristic near-infrared spectra revealed that the quality of artificially aged A. argyi leaves was similar to that of naturally aged A. argyi leaves. In the mouse model, artificially and naturally aged A. argyi leaves not only improved the symptoms of UC with the same therapeutic effects, but also safeguarded the barrier of the colonic mucosa and prevented the release of colitis-related substances. In addition, the content of caffeic acid converted from L-phenylalanine in A. argyi leaves increased during the aging process. CONCLUSION: Conditions for artificial aging of A. argyi leaves were identified for the first time, and the equivalent efficacy of artificially aged A. argyi leaves and naturally aged A. argyi leaves for improving UC was confirmed. This method for artificial aging of A. argyi leaves not only reduces the time and cost associated with this process, but also provides technical support to ensure the quality and stability of artificially aged A. argyi leaves. In addition, caffeic acid was identified as a potential quality-marker for establishing standards and specifications for aging A. argyi leaves for the first time, and its possible transformation mechanism was preliminarily elucidated.

Umpolung reactivity of strained C-C σ-bonds without transition-metal catalysis.

Umpolung is an old and important concept in organic chemistry, which significantly expands the chemical space and provides unique structures. While, previous research focused on carbonyls or imine derivatives, the umpolung reactivity of polarized C-C σ-bonds still needs to explore. Herein, we report an umpolung reaction of bicyclo[1.1.0]butanes (BCBs) with electron-deficient alkenes to construct the C(sp3)-C(sp3) bond at the electrophilic position of C-C σ-bonds in BCBs without any transition-metal catalysis. Specifically, this transformation relies on the strain-release driven bridging σ-bonds in bicyclo[1.1.0]butanes (BCBs), which are emerged as ene components, providing an efficient and straightforward synthesis route of various functionalized cyclobutenes and conjugated dienes, respectively. The synthetic utilities of this protocol are performed by several transformations. Preliminary mechanistic studies including density functional theory (DFT) calculation support the concerted Alder-ene type process of C-C σ-bond cleavage with hydrogen transfer. This work extends the umpolung reaction to C-C σ-bonds and provides high-value structural motifs.

Molecular classification reveals the sensitivity of lung adenocarcinoma to radiotherapy and immunotherapy: multi-omics clustering based on similarity network fusion.

BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.

Pharmacokinetic and bioequivalence study of two capecitabine tablets in Chinese patients with solid tumor cancer.

Capecitabine (CAP) is one of the fluoropyrimidine deoxynucleoside carbamates, which can be converted to 5-fluorouracil (5-FU) by thymine deoxynucleoside phosphorylase (dThdPase) to exert antitumor effects. The purpose of this study is to compare the pharmacokinetics (PK), bioequivalence (BE), and safety of two CAP tablets in Chinese patients with solid tumor cancer. The results showed that the geometric mean ratios (GMRs) of Cmax, AUC0-t and AUC0-∞ of CAP T/R reagent were 90.26%, 95.27%, and 95.07, respectively. The values and 90% confidence intervals (CI) of AUC0-t, AUC0-∞, and Cmax all fall within the range of 80.00-125.00%. In addition, a total of 22 subjects in this study had 30 adverse events, with an incidence of 45.83%, and there were no serious adverse events and adverse events that led to withdrawal from the trial.

Research on plasma modified fly ash denitration.

The effects of reactor parameters and process parameters on the denitration rate of modified fly ash in different gas atmospheres were studied by using a dielectric barrier plasma reactor and using orthogonal experiments. The characteristics of modified fly ash were analyzed using scanning electron microscope, specific surface area analyzer, X-ray diffraction, Boehm titration and Fourier transform infrared spectroscopy. The experimental data were processed by variance analysis and linear regression to induce the denitration mechanism. R2 of the linear regression analysis model is 0.789, which means that the adsorption pore size, acid groups and basic group can explain 78.9% of the change in denitration rate. The basic group will have a significant positive impact on the denitration rate, and the adsorption pore size and acidic group will have a significant negative impact on the denitration rate. Through variance analysis of the experimental data, it was found that the input power and discharge gap have a significant effect on the denitration rate, but the ionization time and discharge length have no significant effect. The input power affects the denitration rate by impacting the basic group, and the discharge gap affects the denitration rate by influencing the adsorption pore size. There are three denitration mechanisms on the surface of fly ash: physical adsorption, chemical adsorption and absorption process. Among them, chemical adsorption is the main mechanism of action, accounting for approximately 60.86%.

Renal aging and mitochondrial quality control.

Mitochondria are dynamic organelles that participate in different cellular process that control metabolism, cell division, and survival, and the kidney is one of the most metabolically active organs that contains abundant mitochondria. Perturbations in mitochondrial homeostasis in the kidney can accelerate kidney aging, and maintaining mitochondrial homeostasis can effectively delay aging in the kidney. Kidney aging is a degenerative process linked to detrimental processes. The significance of aberrant mitochondrial homeostasis in renal aging has received increasing attention. However, the contribution of mitochondrial quality control (MQC) to renal aging has not been reviewed in detail. Here, we generalize the current factors contributing to renal aging, review the alterations in MQC during renal injury and aging, and analyze the relationship between mitochondria and intrinsic renal cells. We also introduce MQC in the context of renal aging, and discuss the study of mitochondria in the intrinsic cells of the kidney, which is the innovation of our paper. In addition, during kidney injury and repair, the specific functions and regulatory mechanisms of MQC systems in resident and circulating cell types remain unclear. Currently, most of the studies we reviewed are based on animal and cellular models, the relationship between renal tissue aging and mitochondria has not been adequately investigated in clinical studies, and there is still a long way to go.

Nitrovin (difurazone), an antibacterial growth promoter, induces ROS-mediated paraptosis-like cell death by targeting thioredoxin reductase 1 (TrxR1).

Glioblastoma multiforme (GBM) is one of the most lethal malignant tumors in the human brain, with only a few chemotherapeutic drugs available after surgery. Nitrovin (difurazone) is widely used as an antibacterial growth promoter in livestock. Here, we reported that nitrovin might be a potential anticancer lead. Nitrovin showed significant cytotoxicity to a panel of cancer cell lines. Nitrovin induced cytoplasmic vacuolation, reactive oxygen species (ROS) generation, MAPK activation, and Alix inhibition but had no effect on caspase-3 cleavage and activity, suggesting paraptosis activation. Nitrovin-induced cell death of GBM cells was significantly reversed by cycloheximide (CHX), N-acetyl-l-cysteine (NAC), glutathione (GSH), and thioredoxin reductase 1 (TrxR1) overexpression. Vitamins C and E, inhibitors of pan-caspase, MAPKs, and endoplasmic reticulum (ER) stress failed to do so. Nitrovin-triggered cytoplasmic vacuolation was reversed by CHX, NAC, GSH, and TrxR1 overexpression but not by Alix overexpression. Furthermore, nitrovin interacted with TrxR1 and significantly inhibited its activity. In addition, nitrovin showed a significant anticancer effect in a zebrafish xenograft model, which was reversed by NAC. In conclusion, our results showed that nitrovin induced non-apoptotic and paraptosis-like cell death mediated by ROS through targeting TrxR1. Nitrovin might be a promising anticancer lead for further development.

m6A RNA methylation modification is involved in the disease course of heart failure.

We explored N6-methyladenosine (m6A) RNA methylation as one of the gene regulatory mechanisms in heart failure (HF) biology. Understanding the different physiological mechanisms will facilitate the prevention and individualized treatment of HF. The Gene Expression Omnibus (GEO) database served as the source of the data. In GSE116250, differential analysis between ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM) and controls yielded differentially expressed m6A regulators. Differential analysis between HF and controls in GSE131296 identifies m6A-modified genes and then performs enrichment analysis. Protein-protein interaction (PPI) network analysis was performed for the differentially expressed ICM- or DCM-associated genes in GSE116250 and GSE55296, respectively. Finally, the diagnostic genes for ICM and DCM were predicted using receiver operating characteristic (ROC) curve. YTHDC1, HNRNPC and HNRNPA2B1 were significantly downregulated in GSE116250 in DCM and ICM compared with controls. A total of 195 genes were identified in GSE131296 as subject to m6A alteration. These genes may play a role in HF through the MAPK signaling pathway and p53 signaling pathway. PPI network analysis identified CCL5, CXCR4 and CCL2 as key genes for ICM and IL-6 as a key gene for DCM. Through ROC curves, we identified m6A-modified APLP1, KLF2 as potential diagnostic genes for ICM, and m6A-modified FGF7, FREM1 and C14orf132 as potential diagnostic genes for DCM. Our findings support m6A modifying mechanisms in HF etiology that contribute to the treatment of HF. Thus, our data suggest that m6A methylation may be an interesting target for therapeutic intervention.

Screening of Active Ingredients from Wendan Decoction in Alleviating Palmitic Acid-Induced Endothelial Cell Injury.

(1) Objective: Traditional Chinese medicine (TCM) plays an important role in the treatment of numerous illnesses. As a classic Chinese medicine, Wendan Decoction (WDD) encompasses a marvelous impact on the remedy of hyperlipidemia. It is known that hyperlipidemia leads to cardiovascular injury, therefore anti-vascular endothelial cell injury (AVECI) may be an underlying molecular mechanism of WDD in the cure of hyperlipidemia. However, there is no relevant research on the effect of WDD on vascular endothelial cells and its pharmacodynamic substances. Therefore, the purpose of this study was to investigate the protective effect of WDD on vascular endothelial cells. (2) Methods: The chemical constituents of WDD were determined by LC-MS/MS technology. The protective effects of 16 batches of WDD on samples from human umbilical vein endothelial cells (HUVECs) were evaluated. Finally, gray relation analysis (GRA) and partial least squares regression (PLSR) were used to analyze the potential correlation between chemical ingredients and AVECI. (3) Results: The results indicated that WDD had apparent protective effect on endothelial cells, and pharmacological properties in 16 batches of WDD tests were apparently discrepant. The GRA and PLSR showed that trigonelline, liquiritin, hesperidin, hesperetin, scopoletin, morin, quercetin, isoliquiritigenin, liquiritigenin and formononetin may be the active ingredients of AVECI in WDD. (4) Conclusions: WDD has a protective effect on endothelial cell injury induced by palmitic acid, which may be related to its component content. This method was suitable for the search of active components in classical TCM.

Copper-Catalyzed Hydroamination of gem-Difluoroalkenes Access to Diversified α-Difluoromethyl Amines.

The difluoromethyl group (CF2H) is of great importance in medicinal chemistry. We report herein an efficient method for the synthesis of diversified α-difluoromethyl amines through copper-catalyzed hydroamination of gem-difluoroalkenes, where the C-N bond formed via a α-CF2H transition-metal intermediate. This new reaction proceeds through Cu-H insertion to gem-difluoroalkenes and gives valuable alkyl-CF2H-containing compounds, which overcome the much more challenged ß-F elimination from α-fluoroalkyl organocopper species. The reaction exhibits broad substrate scope with readily available starting materials and commercial catalysis.

Circulating galectin-3 promotes tumor-endothelium-adhesion by upregulating ICAM-1 in endothelium-derived extracellular vesicles.

The adhesion of tumor cells to vascular endothelial cells is an important process of tumor metastasis. Studies have shown that tumor could educate vascular endothelial cells to promote tumor metastasis through many ways. However, the effect of tumor cells on the functions of vascular endothelial cells-derived extracellular vesicles (H-EVs) and the mechanisms underlying their effects in tumor-endothelium adhesion in metastasis remain mysterious. In this study, we found that H-EVs promoted the adhesion of triple negative breast cancer cell to endothelial cells and cirGal-3 enhanced the adhesion-promoting effects of H-EVs. The underlying mechanism was related to the upregulation of glycolysis in endothelial cells induced by cirGal-3 which led to the increase of the ICAM-1 expression and its transmission to MDA-MB-231 cells by H-EVs. Targeting of cirGal-3 or glycolysis of vascular endothelium in breast cancer therefore represents a promising therapeutic strategy to reduce metastasis.

DSC2 Suppresses the Metastasis of Gastric Cancer through Inhibiting the BRD4/Snail Signaling Pathway and the Transcriptional Activity of ß-Catenin.

Downregulated DSC2 involved in the metastasis of cancers. Unfortunately, its role on the development of gastric cancer (GC) and the potential mechanisms remain unclear. Bioinformatics analysis, Western blot, qRT-PCR, and immunohistochemistry were performed to detect the DSC2 levels of human GC and normal stomach tissues. The role of DSC2 and the downstream signaling in gastric carcinogenesis were explored by using GC specimens, GC cells with different DSC2 expression, inhibitors, and mouse metastasis models. We found that the level of DSC2 decreased significantly in GC tissues and cells. Recovered DSC2 inhibited the invasion and migration of GC cells both in culture and in xenografts. Mechanistically, DSC2 could not only decrease Snail level and nuclear BRD4 level by forming DSC2/BRD4, but also inhibit nuclear translocation of ß-catenin. We concluded that DSC2 inhibited the metastasis of GC, and the underlying mechanisms were closely related to the regulation on nuclear translocation of BRD4 and ß-catenin. Our results suggest that DSC2 may serve as a novel therapeutic target for GC.

Preventive effect of Atractylodis Rhizoma extract on DSS-induced acute ulcerative colitis through the regulation of the MAPK/NF-κB signals in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Atractylodes lancea (Thunb.) DC. is traditionally used as a folk medicine for treating gastrointestinal diseases in China. Nevertheless, the effect and mechanisms of its anti-inflammatory activity on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) have not yet been fully investigated. AIM OF THE STUDY: This study aimed to explore the therapeutic effect and underlying molecular mechanisms of Ethanolic Extract of Atractylodis Rhizoma (EEAR) on DSS-induced UC mice and LPS-induced RAW264.7 cells. MATERIALS AND METHODS: The EEAR was obtained and then analyzed by HPLC analysis. The protective effect of EEAR on DSS-induced UC was evaluated by weight loss, disease activity index (DAI) score, spleen index, goblet cell loss, colon length shortening, myeloperoxidase (MPO) activity and pathological changes. The level of inflammatory cytokines were detected by immunohistochemistry (IHC) and RT-PCR analysis. The expressions of the tight junction (TJ, such as ZO-1, Occludin) proteins and the target proteins in mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) were determined by western blotting analysis. RESULTS: EEAR significantly attenuated the symptoms of UC, suppressed the colon MPO activity, and increased the goblet cell loss. In addition, EEAR could significantly increase the expression of TJs in UC mice. Meanwhile, EEAR treatment could reduce the levels of inflammatory cytokines and inhibit the phosphorylation of MAPK and NF-κB signaling pathways in UC mice and in LPS-induced RAW264.7 cells. CONCLUSION: Our results indicated that EEAR ameliorated DSS-induced UC by inhibiting the inflammatory response and maintaining the intestinal barrier function via modulation of MAPK/NF-κB pathways, thus, EEAR might be a promising therapeutic candidate for UC therapy.

Psoralidin, a natural compound from Psoralea corylifolia, induces oxidative damage mediated apoptosis in colon cancer cells.

Psoralidin (PSO) is a natural coumarin isolated from the seeds of Psoralea corylifolia Linn. Previous studies have reported that PSO exerts numerous pharmacological bioactivities including antitumor. The present study aimed to investigate its anticancer effect using colon cancer cells. Cultured HT-29 and HCT-116 colon cancer cells were treated with different concentrations of PSO, and the cell viability, the intracellular reactive oxygen species (ROS), the protein expression, and the apoptosis were determined by MTT assay, DCFH2 -DA fluorescence probe, Western blotting, and Annexin V/7-AAD staining, respectively. The activities of caspase 3/7 were determined by a commercial kit. Our study found that PSO effectively induces apoptotic cell death mediated by caspase 3/7 in HT-29 and HCT-116 colon cancer cells. PSO treatment rapidly boosts the ROS generation, which is responsible for the PSO-triggered DNA damage, mitochondria membrane potential decrease and caspase 3/7 activation, and c-Jun N-terminal kinase 1/2 activation. Collectively, these results showed that PSO triggered oxidative damage mediated apoptosis in colon cancer cells.

Modified citrus pectin inhibits breast cancer development in mice by targeting tumor-associated macrophage survival and polarization in hypoxic microenvironment.

Large amounts of tumor-associated macrophages (TAM), which are predominately localized in hypoxia area of the tumor tissue, are associated with the malignant progression of the tumor. In the present study, we investigated the inhibitory effects of modified citrus pectin (MCP), a natural dietary polysaccharide, on the survival and polarization of TAM in relation to its inhibition on the growth and migration of breast cancer. M2 macrophages polarized from human monocyte THP-1 were chosen as a model for TAM. We showed that MCP (0.06%-1%) concentration-dependently suppressed the survival of TAM through inhibiting glucose uptake with a greater extent in hypoxia than in normoxia. Furthermore, MCP treatment decreased ROS level in TAM through its reducibility and inhibiting galectin-3 expression, leading to inhibition of glucose transporter-1 expression and glucose uptake. In addition, MCP suppressed M2-like polarization via inhibiting STAT3 phosphorylation. Moreover, the tumor-promoting effect of TAM could be restrained by MCP treatment as shown in human breast cancer MDA-MB-231 cells in vitro and in mouse breast cancer 4T1-luc orthotopic and metastasis models. In both tumor tissue and lung tissue of the mouse tumor models, the number of TAM was significantly decreased after MCP treatment. Taken together, MCP may be a promising agent for targeting TAM in tumor hypoxic microenvironment for breast cancer treatment.

Hyaluronic Acid-Modified Nanoparticles Self-Assembled from Linoleic Acid-Conjugated Chitosan for the Codelivery of miR34a and Doxorubicin in Resistant Breast Cancer.

In this study, a chitosan-based, self-assembled nanosystem that codelivered microRNA34a (miR34a) and doxorubicin (Dox) with hyaluronic acid (HA) modification (named CCmDH NPs) was developed to reverse the resistance of breast cancer (BCa) cells to Dox. The CCmDH NPs had a diameter of 180 ± 8.3 nm and a ζ potential of 16.5 mV with a slow-release effect for 96 h. The codelivery system could protect miR34a from nuclease and serum degradation and transport miR34a and Dox into drug-resistant MCF-7/A cells. In addition, the CCmDH NPs could inhibit proliferation and promote apoptosis by regulating the protein expression of B-cell lymphoma-2 (Bcl-2) and poly(ADP-ribose) polymerase (PARP) and inhibit invasion, metastasis, and adhesion by regulating E-cadherin, N-cadherin, MMP2, CD44, and Snail molecules. The CCmDH NPs induced a 73.7% tumor reduction in xenograft tumor growth in nude mice in vivo. This study provides evidence for the anticancer activity of CCmDH NPs carrying Dox and miR34a in BCa, especially metastatic Dox-resistant BCa models.

Combination therapy with miR34a and doxorubicin synergistically inhibits Dox-resistant breast cancer progression via down-regulation of Snail through suppressing Notch/NF-κB and RAS/RAF/MEK/ERK signaling pathway.

Resistance to breast cancer (BCa) chemotherapy severely hampers the patient's prognosis. MicroRNAs provide a potential therapeutic prospect for BCa. In this study, the reversal function of microRNA34a (miR34a) on doxorubicin (Dox) resistance of BCa and the possible mechanism was investigated. We found that the relative level of miR34a was significantly decreased in Dox-resistant breast cancer cell MCF-7 (MCF-7/A) compared with Dox-sensitive MCF-7 cells. Transfection with miR34a significantly suppressed the invasion, migration, adhesion of MCF-7/A cells without inhibiting their growth obviously. The combination of miR34a and Dox could significantly inhibit the proliferation, migration, invasion and induce the apoptosis of MCF-7/A cells. The synergistic effect of this combination on resistant MCF-7/A cells has no obvious relation with the expressions of classical drug-resistant proteins P-GP, MRP and GST-π, while closely related with the down-regulation on TOP2A and BCRP. Moreover, we found both protein and mRNA expression of Snail were significantly up-regulated in MCF-7/A cells in comparison with MCF-7 cells. Transfection with small interfering RNA (siRNA) of Snail could inhibit the invasion, migration and adhesion of drug-resistant MCF-7/A cells, while high-expression of Snail could remarkably promote the invasion, migration and adhesion of MCF-7 cells, which might be related with regulation of N-cadherin and E-cadherin. Transfection with miR34a in MCF-7/A cells induced a decrease of Snail expression. The potential binding sites of miR34a with 3' UTR of Snail were predicted by miRDB target prediction software, which was confirmed by luciferase reporter gene method. Results showed that the relative activity of luciferase was reduced in MCF-7/A cells after co-transfection of miR34a and wild type (wt)-Snail, while did not change by co-transfection with miR34a and 3' UTR mutant type (mut) Snail. Combination of miR34a and Dox induced a stronger decrease of Snail in MCF-7/A cells in comparison to miR34a or Dox treatment alone. What' more, for the first time, we also found miR34a combined with Dox could obviously inhibit the expression of Snail through suppressing Notch/NF-κB and RAS/RAF/MEK/ERK pathway in MCF-7/A cells. In vivo study indicated that combination of miR34a and Dox significantly slowed down tumor growth in MCF-7/A nude mouse xenograft model compared with Dox alone, which was manifested by the down-regulation of Snail and pro-apoptosis effect in tumor xenografts. These results together underline the relevance of miR34a-driven regulation of Snail in drug resistance and co-administration of miR34a and Dox may produce an effective therapy outcome in the future in clinic.

Potential Therapeutic Strategies for Targeting Y-Box-Binding Protein 1 in Cancers.

As one of the most conservative proteins in evolution, Y-box-binding protein 1 (YB-1) has long been considered as a potential cancer target. YB-1 is usually poorly expressed in normal cells and exerts cellular physiological functions such as DNA repair, pre-mRNA splicing and mRNA stabilizing. In cancer cells, the expression of YB-1 is up-regulated and undergoes nuclear translocation and contributes to tumorigenesis, angiogenesis, tumor proliferation, invasion, migration and chemotherapy drug resistance. During the past decades, a variety of pharmacological tools such as siRNA, shRNA, microRNA, circular RNA, lncRNA and various compounds have been developed to target YB-1 for cancer therapy. In this review, we describe the physiological characteristics of YB-1 in detail, highlight the role of YB-1 in tumors and summarize the current therapeutic methods for targeting YB-1 in cancer.