Curcumin inhibits proliferation of hepatocellular carcinoma cells by blocking PTPN1 and PTPN11 expression.

The antitumor mechanism of curcumin is unclear, especially in hepatocellular carcinoma (HCC) cells. To clarify the mechanism of action of curcumin in the effective treatment of HCC, the targets of curcumin were screened and validated. Candidate genes of curcumin for HCC were screened using the traditional Chinese medicine systems pharmacology (TCMSP) database and validated using The Cancer Genome Atlas (TCGA) database. The correlation of mRNA expression levels between key candidate genes was identified in the TCGA liver hepatocellular carcinoma (LIHC) dataset. The effects on prognosis were analyzed to identify the target gene of curcumin, which inhibits HCC cell proliferation. Based on the subcutaneous xenograft model of human HCC in nude mice, the expression levels of target proteins were observed using immunohistochemistry. The analysis results of the present study identified the target genes of curcumin, which were obtained by screening the TCSMP database. The protein tyrosine phosphatase non-receptor type 1 (PTPN1) was obtained from TCGA database analysis of the targeted genes. The expression levels of PTPN1 and its homologous sequence genes in TCGA LIHC project was analyzed to identify the potential target gene of curcumin, for use in HCC treatment. Next, xenograft experiments were performed to investigate the therapeutic effects of curcumin in an animal model. Curcumin was demonstrated to inhibit the growth of HCC xenograft tumors in mice. Immunohistochemistry results demonstrated that the protein expression levels of PTPN1 and PTPN11 in the curcumin group were significantly lower compared with those in the control group. In conclusion, these results demonstrated that curcumin inhibits the proliferation of HCC cells by inhibiting the expression of PTPN1 and PTPN11.

Construction of magnetic drug delivery system and its potential application in tumor theranostics.

Magnetic nanoparticles(NPs) are characterized by a rich variety of properties. Because of their excellent physical and chemical properties, they have come to the fore in biomedicine and other fields. The magnetic NPs were extensively studied in magnetic separation of cells, targeted drug delivery, tumor hyperthermia, chemo-photothermal therapy, magnetic resonance imaging (MRI) and other biomedical fields. Magnetic NPs are increasingly used in magnetic resonance imaging (MRI) based on their inherent magnetic targeting, superparamagnetic enzyme-like catalytic properties and nanoscale size. Poly(lactic-co-glycolic acid) (PLGA) is a promising biodegradable material approved by FDA and EU for drug delivery. Currently, PLGA-based magnetic nano-drug delivery systems have attracted the attention of researchers. Herein, we achieved the effective encapsulation of sized-controlled polyethylene glycol-3,4-dihydroxy benzyl-amine-coated superparamagnetic iron oxide nanoparticles (SPIO NPs) and euphorbiasteroid into PLGA nanospheres via a modified multiple emulsion solvent evaporation method (W1/O2/W2). NPs with narrow size distribution and acceptable magnetic properties were developed that are very useful for applications involving cancer therapy and MRI. Furthermore, SPIO-PLGA NPs enhanced the MRI T2 relaxation properties of tumor sites.The prepared SPIO NPs and magnetic PLGA nanospheres can be promising magnetic drug delivery systems for tumor theranostics. This study has successfully constructed a tumor-targeting and magnetic-targeting smart nanocarrier with enhanced permeability and retention, multimodal anti-cancer therapeutics and biodegradability, which could be a hopeful candidate for anti-tumor therapy in the future.

Acceptor Planarization and Donor Rotation: A Facile Strategy for Realizing Synergistic Cancer Phototherapy via Type I PDT and PTT.

Tumor hypoxia seriously impairs the therapeutic outcomes of type II photodynamic therapy (PDT), which is highly dependent upon tissue oxygen concentration. Herein, a facile strategy of acceptor planarization and donor rotation is proposed to design type I photosensitizers (PSs) and photothermal reagents. Acceptor planarization can not only enforce intramolecular charge transfer to redshift NIR absorption but also transfer the type of PSs from type II to type I photochemical pathways. Donor rotation optimizes photothermal conversion efficiency (PCE). Accordingly, three 3,6-divinyl-substituted diketopyrrolopyrrole (DPP) derivatives, 2TPAVDPP, TPATPEVDPP, and 2TPEVDPP, with different number of rotors were prepared. Experimental results showed that three compounds were excellent type I PSs, and the corresponding 2TPEVDPP nanoparticles (NPs) with the most rotors possessed the highest PCE. The photophysical properties of 2TPEVDPP NPs are particularly suitable for in vivo NIR fluorescence imaging-guided synergistic PDT/PTT therapy. The proposed strategy is helpful for exploiting type I phototherapeutic reagents with high efficacy for synergistic PDT and PTT.

Molecular interplay between linc01134 and YY1 dictates hepatocellular carcinoma progression.

BACKGROUND: Revealing the mechanical role of long non-coding RNAs (lncRNAs) in tumorigenesis can contribute to novel therapeutic target for cancers. The regulatory role of linc01134 in hepatocellular carcinoma (HCC) has not been studied yet. MATERIALS AND METHODS: qRT-PCR and western blot were conducted to measure relevant RNA and protein expressions. CCK-8, colony formation, EdU, flow cytometry, wound-healing, transwell assays and xenograft experiments were performed to determine the role of linc01134 in HCC. ChIP and luciferase reporter assays were performed to analyze the effects of Yin Yang-1 (YY1) on linc01134 transcription activity. Relevant mechanical experiments were performed to verify interaction between relative genes. RESULTS: YY1 enhanced linc01134 transcription by interacting with linc01134 promoter. Knockdown of linc01134 inhibited proliferation, migration and epithelial-mesenchymal transition (EMT), yet promoting apoptosis in HCC cells. Mechanically, linc01134 acted as miR-324-5p sponge and interacted with insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to increase the stability of YY1 mRNA expression. Up-regulated YY1 continuously stimulated linc01134 expression by enhancing linc01134 promoter activity, forming a positive feedback loop. CONCLUSION: Linc01134/miR-324-5p/IGF2BP1/YY1 feedback loop mediates HCC progression, which possibly provide prognosis and treatment target of HCC.

Ginsenoside Rg3 regulates DNA damage in non-small cell lung cancer cells by activating VRK1/P53BP1 pathway.

Lung cancer is the leading cause of cancer-related deaths. Ginsenoside Rg3 is the main ingredient of Ginseng which is used to treat non-small cell lung cancer (NSCLC). It has been found to enhance the efficiency of chemotherapy thereby reducing its side effects. Previous studies found that ginsenoside Rg3 can reduce the occurrence of NSCLC by inducing DNA damage. Yet, its anti-DNA damaging effects and mechanisms in tumor cells are still not fully understood. This study explored the effect of ginsenoside Rg3 on DNA repair and VRK1/P53BP1 signaling pathway. Ginsenoside Rg3 treatment significantly decreased the incidence and invasionin a mouse model of lung cancer induced by urethane. The results of cell survival assay and single cell gel electrophoresis showed that ginsenoside Rg3 protected lung adenocarcinoma cells from DNA damage as well as inhibited the proliferation of tumor cells. Ginsenoside Rg3 increased the mRNA and protein expression of VRK1 in NSCLC cells as measured by RT-qPCR and western blot, respectively. These findings suggests that ginsenoside Rg3 regulates VRK1 signaling. Immunofluorescence assays showed that P53BP1 and VRK1 protein level increased, and the VRK1 protein translocated between the nuclei and cytoplasm. Finally, this conclusion was confirmed by the reverse validation in VRK1-knockdown cells. Taken together, these results show that ginsenoside Rg3 upregulate VRK1 expression and P53BP1 foci formation in response to DNA damage thereby inhibiting the tumorigenesis and viability of cancer cells. These findings reveal the role of Rg3 in lung cancer and provides therapeutic targets for developing new drugs in the prevention and treatment of lung cancer.

Monodisperse Au-Fe2C Janus Nanoparticles: An Attractive Multifunctional Material for Triple-Modal Imaging-Guided Tumor Photothermal Therapy.

Imaging-guided photothermal therapy (PTT) by combination of imaging and PTT has been emerging as a promising therapeutic method for precision therapy. However, the development of multicomponent nanoplatforms with stable structures for both PTT and multiple-model imaging remains a great challenge. Herein, we synthesized monodisperse Au-Fe2C Janus nanoparticles (JNPs) of 12 nm, which are multifunctional entities for cancer theranostics. Due to the broad absorption in the near-infrared range, Au-Fe2C JNPs showed a significant photothermal effect with a 30.2% calculated photothermal transduction efficiency under 808 nm laser irradiation in vitro. Owing to their excellent optical and magnetic properties, Au-Fe2C JNPs were demonstrated to be advantageous agents for triple-modal magnetic resonance imaging (MRI)/multispectral photoacoustic tomography (MSOT)/computed tomography (CT) both in vitro and in vivo. We found that Au-Fe2C JNPs conjugated with the affibody (Au-Fe2C-ZHER2:342) have more accumulation and deeper penetration in tumor sites than nontargeting JNPs (Au-Fe2C-PEG) in vivo. Meanwhile, our results verified that Au-Fe2C-ZHER2:342 JNPs can selectively target tumor cells with low cytotoxicity and ablate tumor tissues effectively in a mouse model. In summary, monodisperse Au-Fe2C JNPs, used as a multifunctional nanoplatform, allow the combination of multiple-model imaging techniques and high therapeutic efficacy and have great potential for precision theranostic nanomedicines.

Effect of coffee consumption on the risk of gastric cancer: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND AND OBJECTIVES: Results from observational epidemiologic studies on the relationship between coffee consumption and gastric cancer are inconsistent and inconclusive. To assess the association between coffee consumption and the risk of gastric cancer, we summarized evidence from prospective cohort studies. METHODS: Relevant studies were retrieved through computer searches (PubMed, EmBase and the Cochrane Library) and a review of references up to December 2014. The quality of the included studies was evaluated by Newcastle-Ottawa quality assessment scale. We used a meta-analytic approach to estimate overall hazard ratios (HRs) and 95% confidence intervals (CIs) for regular coffee drinkers versus individuals who seldom drank coffee. Sensitivity analysis and subgroup analysis were performed to assess the reliability of our results. A dose-response analysis was performed to assess the risk of gastric cancer based on the level of coffee consumption. RESULTS: Nine prospective cohort studies involving 1,250,825 participants and 3027 gastric cancer cases were included in this meta-analysis. The pooled HR of gastric cancer for the study-specific regularly versus seldom coffee drinking categories was 1.05 (95% CI, 0.88 to 1.25) with significant heterogeneity across studies (I(2) = 74.0%, P = 0.000). After the sensitivity analysis, three studies were deleted; however the association remained insignificant (HR, 0.99; 95% CI, 0.91 to 1.08). Subgroup analysis by anatomic location showed a risk for coffee consumption associated with cardia cancer (HR, 1.23; 95% CI, 1.04 to 1.45; heterogeneity, I(2) = 36.4, P = 0.207). In the dose-response analysis, there was no significant association between coffee intake (in cups) and the risk of gastric cancer (P for linearity trend and non-linearity > 0.05). CONCLUSION: Our meta-analysis demonstrated that coffee consumption was not associated with overall gastric cancer risk; however, coffee consumption may be a risk factor for gastric cardia cancer.

Resveratrol-4-O-D-(2'-galloyl)-glucopyranoside isolated from Polygonum cuspidatum exhibits anti-hepatocellular carcinoma viability by inducing apoptosis via the JNK and ERK pathway.

Resveratrol-4-O-D-(2'-galloyl)-glucopyranoside (RESG) is one of the active compounds isolated from Polygonum cuspidatum. The purpose of our present study was to investigate the anti-hepatocellular carcinoma effect of RESG in vitro and in vivo, and the possible mechanisms in vitro. In vitro, our results showed that RESG could significantly inhibit the human hepatocellular carcinoma viability in the MTT assay, in a dose- and time-dependent manner. Furthermore, our results demonstrated that RESG could induce SMMC-7721 cell apoptosis and activate caspases 3 and caspases 9 by using Annexin V-FITC staining and western blot, respectively. In vivo, RESG also showed efficacy in SMMC-7721 xenograft model in nude mice, and further molecule mechanisms were investigated in vitro. The results showed that RESG up-regulated the p-JNK expressions, whereas it down-regulated the p-ERK expressions. Above results demonstrated that RESG is a potential therapeutic agent for hepatocellular carcinoma via JNK and ERK pathway to induce apoptosis. Our finding provided a basis for further development of RESG as an anticancer agent.

Puerarin induces mitochondria-dependent apoptosis in hypoxic human pulmonary arterial smooth muscle cells.

BACKGROUND: Pulmonary vascular medial hypertrophy in hypoxic pulmonary arterial hypertension (PAH) is caused in part by decreased apoptosis in pulmonary artery smooth muscle cells (PASMCs). Puerarin, an isoflavone purified from the Chinese medicinal herb kudzu, ameliorates chronic hypoxic PAH in animal models. Here we investigated the effects of puerarin on apoptosis of hypoxic human PASMCs (HPASMCs), and to determine the possible underlying mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: HPASMCs were cultured for 24 h in normoxia or hypoxia (5% O2) conditions with and without puerarin. Cell number and viability were determined with a hemacytometer or a cell counting kit. Apoptosis was detected with a TUNEL test, rhodamine-123 (R-123) fluorescence, a colorimetric assay, western blots, immunohistochemical staining and RT-PCR. Hypoxia inhibited mitochondria-dependent apoptosis and promoted HPASMC growth. In contrast, after puerarin (50 µM or more) intervention, cell growth was inhibited and apoptosis was observed. Puerarin-induced apoptosis in hypoxic HPASMCs was accompanied by reduced mitochondrial membrane potential, cytochrome c release from the mitochondria, caspase-9 activation, and Bcl-2 down-regulation with concurrent Bax up-regulation. CONCLUSIONS/SIGNIFICANCE: Puerarin promoted apoptosis in hypoxic HPASMCs by acting on the mitochondria-dependent pathway. These results suggest a new mechanism of puerarin relevant to the management of clinical hypoxic pulmonary hypertension.