Good Antitumor Effect Research Articles

Enhanced delivery of artesunate by stimuli-responsive polymeric micelles for lung tumor therapy

Artesunate (ART) as a traditional chinese medicine has been reported to have a good antitumor effect on some cancers. However, the poor hydrophilicity and instability in the intestine limit its bioavailability and further application. Herein, this work reported a redox-sensitive micelle system encapsulating ART to enhance the therapeutic effect on lung tumor. Specifically, K5 capsular polysaccharide-SS-d-α-tocopheryl succinate (K5-SS-TOS, KSST) copolymers can self-assemble to form micelles and effectively load ART into the hydrophobic core. Simultaneously, redox-insensitive K5 capsular polysaccharide-d-α-tocopheryl succinate (K5-TOS, KT) copolymers were synthesized as control. ART-loaded micelles (ART/KSST) with a spherical particle size had good polydispersity. The drug loading content and entrapment efficiency of the ART/KSST were (13.5 ± 0.92) % and (81.09 ± 2.61) %, respectively. Moreover, ART/KSST can release ART quickly in the presence of glutathione, showing a good redox release behavior. In addition, the ART loaded micelles had negligible toxicity to normal cells. However, ART/KSST which can be uptaken through energy-dependent pathways by A549 cells showed higher cytotoxicity than ART/KT. The results suggested that disulfide bond can be ruptured in the tumor cells, resulting in disintegration of the micelle structure and fast release of ART to achieve better therapeutic effect. Therefore, the redox-sensitive KSST copolymers as potential nanocarriers can deliver ART effectively to improve the therapeutic effect of lung tumors.

Surface modified cellulose nanocrystalline hybrids actualizing efficient and precise delivery of doxorubicin into nucleus with: In vitro and in vivo evaluation

AbstractRod‐like‐shape nanomedicines with the ability of lysosomal pH‐controlled drug release can precisely deliver doxorubicin (DOX) into its target, nucleus, and can fully exert its anticancer effect. Taking advantage of their large specific surface area, cellulose nanocrystals (CNCs) were used to fabricate pH‐responsive DOX‐loaded rod‐like shaped hybrids nanomedicines: cis‐aconityl‐doxorubicin (CAD)@polyethylenimine (PEI)@CNCs (CAD@PEI@CNCs) via layer‐by‐layer (LbL) assembly. In vitro, CAD@PEI@CNCs hybrids displayed rod‐like shape, high drug loading content, lysosomal pH‐controlled drug release, efficient and precise doxorubicin (DOX) delivering into the nucleus. Moreover, the cellular uptake of CAD@PEI@CNCs hybrids was 20.9 folds higher than that of DOX·HCl against A549 cells. The cytotoxicity of CAD@PEI@CNCs hybrids was much higher than that of DOX·HCl and the pH‐irresponsive hybrids against A549 cell. In vivo, CAD@PEI@CNCs hybrids exhibited good antitumor effect: (42.0 ± 6)% inhibition rate and few harms to the nude mice. Altogether, rod‐like shaped pH‐responsive CAD@PEI@CNCs hybrids nanomedicines could efficiently overcome the vascular and tumor barriers, and precisely deliver DOX to nucleus to convert DOX antitumor effects. These results indicate that CAD@PEI@CNCs have great potential to act as advanced nanomedicines with enhanced delivery efficiency and therapeutic efficiency.

Pharmacologic targeting of the P-TEFb complex as a therapeutic strategy for chronic myeloid leukemia

BackgroundThe positive transcription elongation factor b (P-TEFb) kinase activity is involved in the process of transcription. Cyclin-dependent kinase 9 (CDK9), a core component of P-TEFb, regulates the process of transcription elongation, which is associated with differentiation and apoptosis in many cancer types. Wogonin, a natural CDK9 inhibitor isolated from Scutellaria baicalensis. This study aimed to investigate the involved molecular mechanisms of wogonin on anti- chronic myeloid leukemia (CML) cells.Materials and methodsmRNA and protein levels were analysed by RT-qPCR and western blot. Flow cytometry was used to assess cell differentiation and apoptosis. Cell transfection, immunofluorescence analysis and co-immunoprecipitation (co-IP) assays were applied to address the potential regulatory mechanism of wogonin. KU-812 cells xenograft NOD/SCID mice model was used to assess and verify the mechanism in vivo.ResultsWe reported that the anti-CML effects in K562, KU-812 and primary CML cells induced by wogonin were regulated by P-TEFb complex. We also confirmed the relationship between CDK9 and erythroid differentiation via knockdown the expression of CDK9. For further study the mechanism of erythroid differentiation induced by wogonin, co-IP experiments were used to demonstrate that wogonin increased the binding between GATA-1 and FOG-1 but decreased the binding between GATA-1 and RUNX1, which were depended on P-TEFb. Also, wogonin induced apoptosis and decreased the mRNA and protein levels of MCL-1 in KU-812 cells, which is the downstream of P-TEFb. In vivo studies showed wogonin had good anti-tumor effects in KU-812 xenografts NOD/ SCID mice model and decreased the proportion of human CD45+ cells in spleens of mice. We also verified that wogonin exhibited anti-CML effects through modulating P-TEFb activity in vivo.ConclusionsOur study indicated a special mechanism involving the regulation of P-TEFb kinase activity in CML cells, providing evidences for further application of wogonin in CML clinical treatment.8cwZMBLp1zasMdEPaNEt3gVideo

Smart Polymeric Nanoparticles with pH-Responsive and PEG-Detachable Properties (II): Co-Delivery of Paclitaxel and VEGF siRNA for Synergistic Breast Cancer Therapy in Mice

BackgroundThe dual-loaded nano-delivery system can realize chemotherapeutic drug and small interfering RNA (siRNA) co-loading as well as enhance the therapeutic effect of drugs on tumors through a synergistic effect, while reducing their toxic and side effects on normal tissues.MethodsPreviously, we developed layered smart nanoparticles (NPs) to co-deliver survivin siRNA as well as small molecule drugs for lung cancer. In this study, we used such smart NPs to co-deliver paclitaxel (PTX) and siRNA against vascular endothelial growth factor (VEGF) gene for breast cancer therapy in mice models. For the prepared NPs, characterizations such as particle size, zeta potential, gel electrophoresis imaging and in vitro stability were investigated. Then, 4T1 cells were used to evaluate the in vitro VEGF silencing capacity, tumor cell inhibitory and anti-apoptotic abilities. Finally, an orthotopic model of mouse breast cancer was established to evaluate the in vivo antitumor effects and safety properties of PTX-siRNAVEGF-NPs.ResultsWe prepared PTX-siRNAVEGF-NPs with particle size of 85.25 nm, PDI of 0.261, and zeta potential of 5.25 mV. The NPs with VEGF siRNA effectively knocked down the expression of VEGF mRNA. Cell counting kit-8 (CCK-8) and apoptosis assays revealed that the PTX-siRNAVEGF-NPs exhibited antiproliferation effect of PTX on 4T1 cells. The in vivo anti-tumor study indicated that PTX-siRNAVEGF-NPs could exert an antitumor effect by inhibiting the formation and development of new blood vessels in tumor tissues, thereby cutting off nutrient and blood supplies required for tumor tissue growth. Both the anti-tumor efficacy and in vivo safety of the PTX-siRNAVEGF-NPs group were better than that of the PTX-NPs and siRNAVEGF-NPs groups.ConclusionThe combination of PTX and VEGF siRNA exerts good antitumor effect on 4T1 tumor cells. This study provides a theoretical and practical basis for breast cancer therapy.

Design and identification of two novel resveratrol derivatives as potential LSD1 inhibitors.

Background: Overexpression of LSD1 is associated with the occurrence of many diseases, including cancers, which makes LSD1 a significant target for anticancer drug research. Methodology & Results: With the aid of 3D quantitative structure-activity relationship models established with 34 reported resveratrol derivativeLSD1 inhibitors, derivatives 35-40 were designed. Absorption, distribution, metabolism and excretion calculations showed that they may have good bioavailability and drug likeness. Additionally, 35 and 37 presented good antitumor effects in an in vitro antiproliferative assay. Molecular docking and molecular dynamics simulationresults indicated that 35 and 37 can establish extensive interactions with LSD1. Conclusion: The results of computational prediction and experimental validation suggest that 35 and 37 are effective antitumor inhibitors, which provides some ideas and directions for the development of new anticancer LSD1 inhibitors.

Engineering glutathione-responsive near-infrared polymeric prodrug system for fluorescence imaging in tumor therapy

The release and biodistribution of drugs in the body have an important impact on tumor diagnosis and treatment. Near-infrared (NIR) fluorescent active fluorophores with good photostability are used to detect drug release and perform in vivo imaging. Here, we developed a glutathione-responsive NIR prodrug POEGMA-b-P(CPT-CyOH) (PCC) for effective cancer diagnosis and treatment, whereby the camptothecin (CPT) and NIR fluorophore CyOH in PCC are connected by disulfide bonds. In vitro experiments confirmed that PCC was quickly taken up by cells. The high concentration of tumor intracellular glutathione caused the cleavage of the PCC disulfide bonds, leading to the release of the chemotherapeutic drug CPT, indicating that PCC can promote apoptosis. Moreover, owing to the fluorescent properties of CyOH, PCC was successfully used for in vivo imaging to observe the drug penetration and enrichment capabilities in tumors. Finally, PCC successfully inhibited tumor growth, indicating that the prodrug has a good anti-tumor effect. This work provides new strategies for chemical drug delivery and precise cancer treatment.

Sustained release of Ganoderma lucidum antitumor drugs using a sandwich structured material prepared by electrospinning

In cancer therapy, there still remains great challenges such as controlling cancer metastasis and the side effects from chemotherapy. Many anti-cancer drugs have cytotoxicity to normal cell with a high concentration, on the other hand, the anti-cancer effect will not be ideal if it didn’t reach the effective concentrations. So there is a way to make balance between the cytotoxicity and effective concentrations, sustained release can not only prolong the duration of the effective concentration but also reduce the time of peak concentration. Herein, we designed a sandwich structured antitumor composite with a three-layer film including: i) the top and bottom layers of ethyl cellulose (EC) containing Ganoderma lucidum triterpenes (GLT); ii) the middle layer of polyvinyl alcohol (PVA) containing G. lucidum polysaccharides (GLP). The films were fabricated layer-by-layer using electrospinning with the aim of providing the sustained release of the antitumor activity of GLT and GLP for use in cancer therapy. This sandwich structured material has potential for sustained antitumor release, high loading capacity (1.6% for GLT and 7.9% for GLP) and large surface area. The morphology, structure, biocompatibility, and the release profile of the encapsulated GLP and GLT in this fabricated composite were characterized. The in vitro antitumor effects of this drug film were studied using carcinoma cells, as SGC-7901, A549, Hela and Caco-2, with the IC50 of 51.2, 90.7, 93.0 and 21.7 μg/mL, respectively. In brief, this medical film achieved a good antitumor effect at the cellular level.

Avasimibe Dampens Cholangiocarcinoma Progression by Inhibiting FoxM1-AKR1C1 Signaling.

Avasimibe is a bioavailable acetyl-CoA acetyltransferase (ACAT) inhibitor and shows a good antitumor effect in various human solid tumors, but its therapeutic value in cholangiocarcinoma (CCA) and underlying mechanisms are largely unknown. In the study, we proved that avasimibe retard cell proliferation and tumor growth of CCAs and identified FoxM1/AKR1C1 axis as the potential novel targets of avasimibe. Aldo-keto reductase 1 family member C1 (AKR1C1) is gradually increased along with the disease progression and highly expressed in human CCAs. From survival analysis, AKR1C1 could be a vital predictor of tumor recurrence and prognostic factor. Enforced Forkhead box protein M1 (FoxM1) expression results in the upregulation of AKR1C1, whereas silencing FoxM1 do the opposite. FoxM1 directly binds to promoter of AKR1C1 and triggers its transcription, while FoxM1-binding site mutation decreases AKR1C1 promoter activity. Moreover, over-expressing exogenous FoxM1 reverses the growth retardation of CCA cells induced by avasimibe administration, while silencing AKR1C1 in FoxM1-overexpressing again retard cell growth. Furthermore, FoxM1 expression significantly correlates with the AKR1C1 expression in human CCA specimens. Our study demonstrates a novel positive regulatory between FoxM1 and AKR1C1 contributing cell growth and tumor progression of CCA and avasimibe may be an alternative therapeutic option for CCA by targeting this FoxM1/AKR1C1 signaling pathway.

Research progress on proteasome subunits in regulating occurrence and development of hepatocellular carcinoma.

Proteasome is the eukaryotic organelle responsible for degradation of short-lived proteins and involved in maintaining cellular protein homeostasis. It has been reported that during the occurrence and development of hepatocellular carcinoma (HCC), the regulatory particle subunits of proteasome regulate a series of tumor-related proteins, and proliferation, survival-associated signaling molecules, including PTEN gene, P53, Bcl-2, Bcl-2 interacting mediator of cell death (Bim), cyclin-dependent kinase 4(CDK4), transforming growth factor β receptor (TGFBR), E2F1, growth factor receptor-bound protein 2 (GRB2) . Meanwhile, these subunits regulate some tumor-associated pathway protein, such as signal transducer and activator of transcription 3 (STAT3) and protein kinase B (AKT), inducing their malfunction to promote the occurrence, proliferation, invasion and metastasis of HCC. The core particle subunits are more to perform the degradation of HCC-related proteins, so inhibitors targeting the core particle show a good anti-tumor effect. This review summarizes the current research progress on the regulation and mechanism of proteasome subunits in promoting the occurrence and development .

Anti-tumor Effect of Shikonin on S180 tumor - Bearing Mice

Objective: To investigate the changes of cell cycle and the content of P53 protein in S180 cells by using the specific fluorescent probe to identify the biological target to be measured according to the change of the fluorescence signal. The results showed that Shikonin had good anti-tumor effect. Methods: Cell cycle changes and P53 protein content in S180 cells were detected by flow cytometry. Results: With the increase of Shikonin dose, S180 cells G1 and S phase content gradually increased, it can be inferred Shikonin action in cells, and the cells can be blocked in G1 and S phase. With the increase of the dose of Shikonin, the expression of P53 protein increased. This suggests that Shikonin may up-regulate P53 activity and induce apoptosis. Conclusion: From the experimental results, we can see that Shikonin has a good antitumor effect in vivo.

Research progress in mechanism of berberine's antitumor action

Malignant tumor, an important factor threatening human life and health, brings huge economic burden to patients. At present, chemoradiotherapy is still the main treatment method for tumor diseases, but there are also great side effects when it plays a therapeutic role. Traditional Chinese medicine in the prevention and treatment of tumor diseases has many advantages such as few side effects, improving the physiological state of patients, and slowing down the side effects of radiotherapy and chemotherapy. Berberine is an effective component of rhizoma coptidis, with a very good antitumor effect. It can inhibit tumor cell proliferation, promote tumor cell apoptosis, inhibit tumor metastasis and angiogenesis, regulate tumor autophagy, reverse multi-drug resistance of tumor, regulate the body immunity, and affect tumor metabolic reprogramming to play its role. Compared with chemical preparations, berberine has a wide range of sources, with high safety and easy access, and has great potential in the prevention and treatment of malignant tumors. In this article, we would mainly review the research progress on the antitumor mechanism of berberine in recent years.

Metastable interface biomimetic synthesis of a smart nanosystem for enhanced starvation/gas therapy

Glucose oxidase (GOx)-mediated starvation therapy holds great promise in cancer treatment. However, the worse hypoxia conditions result into low therapeutic efficiency, and undegradability of carriers poses potential threats to living bodies. To address this, herein a bioinspired MnO2 nanosystem with controllable surface was developed for highly efficient starvation/gas synergistic enhanced therapy. Biomimetic design and further surface modification unprecedentedly endowed the nanosystem with ultrahigh loading capacity for GOx and l-Arginine (l-Arg) and special selectivity toward cancer cells. Especially, the dissipative O2 during starvation therapy was well replenished by a positive cycle formed by the nanosystem, which continuously reproduced O2 and accelerated glucose consumption. The abundant H2O2 was further used to oxidize l-Arg into nitric oxide to realize gas therapy. In vitro and in vivo testing confirmed that this new treatment effectively blocked the nutrition and energy sources of cells to obtain excellent therapeutic effect. We reported the first experimental item of this nanosystem for inhibiting cancer cell migration. Considering the novel design concept with facile biomimetic methods, effective co-loading of endogenous substances, and good anti-tumor and anti-migration effects, this work provided new theoretical and experimental basis for starvation therapy and inspired people to design more delicate platform for cancer treatment.

Effect of the polysaccharides derived from Dendrobium officinale stems on human HT-29 colorectal cancer cells and a zebrafish model

Human colorectal cancer (CRC) is treated with 5-fluorouracil (5-Fu). However, this drug causes various adverse effects, suggesting the benefit of developing safer natural-based drugs with high specificity and tolerable adverse effects. Dendrobium officinale has been used as a functional food and important medicine in China for more than a thousand years. The natural polysaccharides obtained from D. officinale (DOPW-1) show inhibitory activity against cancer cells. This study aimed to comparatively investigate the anticancer activity of DOPW-1 and mannose (Mann) on HT-29 cells and explored the possible underlying molecular mechanisms of CRC treatment. HT-29 cells were treated with 5-Fu, DOPW-1, and Mann or their combinations. Cell viability and apoptosis were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Hoechst 33342 with annexin V-fluorescein isothiocyanate/propidium iodide assays, respectively. DOPW-1 showed good antitumor effects on HT-29 cells and significantly potentiated the anticancer activities of 5-Fu in vitro and in vivo. DOPW-1 significantly inhibited tumor metastasis in the zebrafish model. Furthermore, the monosaccharide composition of DOPW-1 might not have an important effect on its antitumor activity. The results of Western blot analysis suggested that DOPW-1 alone and in combination with 5-Fu induced cell apoptosis using the mitochondria-dependent intrinsic apoptotic pathway. Thus, DOPW-1 is a potential source of natural polysaccharides for CRC therapy alone or in combination with 5-Fu.

Baicalin triggers apoptosis, inhibits migration, and enhances anti-tumor immunity in colorectal cancer via TLR4/NF-κB signaling pathway.

Aberrant activation of the nuclear factor-kappa B (NF-κB) signaling pathway is closely implicated in colorectal cancer (CRC) growth, metastasis, and immune escape. In the present study, we reported natural derived compound of baicalin (BA), an efficient inhibitor of NF-κB, with good anti-tumor effect on CRC. CCK8 and colony formation assays showed that Baicalin significantly inhibit viability and proliferation in HCT-116 and CT26 cells. Additionally, Baicalin dramatically triggers mitochondria-mediated apoptosis in both HCT-116 and CT-26 cells, which is evidenced by loss of mitochondrial membrane potential and elevated cellular reactive oxygen species level. Treatment with Baicalin suppresses migration and invasion of CT26 cells by impairing TLR4/NF-κB signaling pathway. What's more, administration of Baicalin significantly retarded tumor growth rate in a subcutaneous xenograft tumor mouse model of CT26 cells. Treatment with Baicalin could ameliorate tumor immunosuppressive environment by downregulation of PD-L1 expression and proportion of myeloid-derived suppressor cells (MDSCs) and upregulation of percent of CD4+ and CD8+ T cells in CT26 tumors, thus improving anti-tumor immunity. In conclusion, our study demonstrated that baicalin triggers apoptosis, inhibits migration, and enhances anti-tumor immunity in colorectal cancer via TLR4/NF-κB signaling pathway, suggesting it might serve as a potential candidate drug for the treatment of CRC. PRACTICAL APPLICATIONS: In the present study, we reported natural derived compound of baicalin (BA), an efficient inhibitor of NF-κB, with good anti-tumor effect on CRC. We demonstrated that baicalin triggers mitochondria-mediated apoptosis, inhibits migration, and improves anti-tumor immunity in colorectal cancer via TLR4/NF-κB signaling pathway.

Cyy260, a Novel Small Molecule JAK2 Inhibitor, Suppresses Cell Growth in Non-Small Cell Lung Cancer

Background: Non-small cell lung cancer (NSCLC) is a malignant tumor that accounts for the most new cancer cases and cancer-related deaths worldwide. It is particularly important to study therapies that target cancer cells and to find low-toxicity, high-efficiency anticancer drugs. Cyy260 is a novel small molecule JAK2 inhibitor with good antitumor effect. Methods: MTT and clone formation experiments were used to evaluate the effect of Cyy260 on cell proliferation. Transwell and scratch experiments were used to evaluate the effect of Cyy260 on cell migration. Flow cytometry was used to detect cell apoptosis and cell cycle changes. Downregulation and overexpression of the JAK2 protein were assessed to study the mechanism of Cyy260 inhibition of JAK2/STAT3 signaling. A xenograft tumor model was used to explore the effect of Cyy260 on tumor growth in vivo. Findings: Cyy260 had a concentration- and time-dependent inhibitory effect on NSCLC cells, regulated apoptosis and inhibited cell proliferation. Further analysis of molecular mechanisms showed that the JAK2/STAT3 signaling pathway was involved in the antitumor effect mediated by Cyy260 in vitro and in vivo. Interpretation: Cyy260 is a novel inhibitor of the JAK2/STAT3 pathway thus may have potential in therapy of NSCLC and other cancers. Funding: This work was financially supported by the National Natural Science Foundation of China (81973168), Natural Science Foundation of Zhejiang Province (LY21H300005 and LQ21H310007) and Wenzhou Municipal Science and Technology Bureau (ZY2020025 and Y20190056). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: All animal studies were performed with an approved protocol by the Institutional Animal Care and Use Committee of Wenzhou Medical University.

Integration of Dual Targeting and Dual Therapeutic Modules Endows Self-Assembled Nanoparticles with Anti-Tumor Growth and Metastasis Functions.

ObjectHigh targeting and efficient cytotoxicity toward tumor cells endow NPs excellent anti-tumor activity. Herein, a peptide polymer possessing dual-targeting ability and double therapeutic activity was developed and named TGMF, which can form NPs through self-assembly. It is composed of four functional modules: 1) Active targeting peptide TMTP1 (T) deliver NPs to tumors specifically; 2) Therapeutic peptide GO-203 (G), which can significantly inhibit tumor growth by disrupting the redox balance in cells; 3) A passively targeted enzyme-responsive peptide PLGLGA (M), which can be cleaved specifically by metalloproteinase-2 (MMP-2) highly expressed in the tumor microenvironment (TME); and 4) Hexadecyl (F), which has strong hydrophobicity, can promote the self-assembly of TGMF NPs.MethodsFive modular peptide probes, namely, TGF, TMF, TGM, GMF, and TGMF were synthesized and self-assembled into NPs in solution. The characterization, enzyme reactivity, and cytotoxicity of NPs were evaluated in vitro, and the pharmacokinetics, bio-distribution, anti-tumor activity of NPs were investigated in vivo. In addition, transcriptome sequencing identified the intracellular signaling pathway-related genes involved in the anti-tumor effect of TGMF.ResultsUpon enzyme cleavage, two types of nanostructure, NPs and nanofibers (NFs), were detected under TEM. Moreover, the cytotoxicity and anti-invasion activity of TGMF against tumor cells used were strongest among the five modular probes examined in vitro. TGMF increased reactive oxygen species (ROS) levels in cytoplasm and produced numerous NFs in extracellular interval and intracellular space. Transcriptome sequencing revealed that TGMF caused 446 genes' down-regulation and 270 genes' up-regulation in HeLa cells. In vivo, TGMF has a good anti-tumor effect, effectively prolonging the survival time of HeLa-tumor-bearing mice without systemic side effects.ConclusionIntegration of multiple functional modules into NPs could be a promising strategy for the future of nanomedicine design towards tumor treatment.

Advances in the Action Mechanism of Classical Pathways IKKα and IKKβ in Hematological Tumors and Drug Therapy Blocking Their Effect--Review

In recent years, it is found that the classical IKKα and IKKβ pathway were closely relates with hematological tumors, except the classical pathogenesis, moreover the classical IKKβ pathway is deeply studied. The studies indicated that the IKKβis activated to phosphorylate the NF-κB through multiple cascades under the effect of extracellular IL-6, TNF-α and other stimulating factors. At the cellular level, the classical IKKβcan promote the tumor cell survival and proliferation, reduce the cell apoptosis, and promote the angiogenesis and cell transfer. Although the classical IKKα plays a role in regulating IKKβ activity, but its role in non-classical pathway is more prominent. This review briefly summarizes the latest advance of researches on the pathogenesis of hematological malignancies in term of IKKα and IKKβpathway, so as to provide the theoretic basis for deeply understanding and studying the pathogenesis of hematologic tumors. At present, blocking the classical IKKα and IKKβ pathway has become a new target for treatment of hematological tumors, moreover, some specific inhibitor for IKKα and IKKβpathway have been developed, for example, LY2409881, BMS 345541 and so on. Most of these drugs are in clinical trials and display some good anti-tumor effects.

Green synthesis of 1,4-dihydropyridines using cobalt carbon nanotubes as recyclable catalysts

Heterocyclic compounds occur widely in nature and in drug molecules. The activity of many nitrogen-containing heterocyclic compounds is unique. For example, 1,4-dihydropyridines display good antitumor and antibacterial effects and can be commercially used as calcium channel blocker agents in the treatment of cardiovascular diseases. To reduce the use of toxic catalysts in the synthesis of 1,4-dihydropyridines, here we designed cobalt carbon nanotubes as a heterogeneous catalyst. We report the efficient synthesis of 1,4-dihydropyridines under mild conditions, which allows to access a wide array of 1,4-dihydropyridines from aromatic aldehyde in high yields, up to 96%. Advantages include the use of ethanol as solvent, low catalyst loading of 6% mol, short reaction time of 5–15 min, easy preparation and recyclable catalyst.

Inhibitory effect of paeoniflorin on IgE-dependent and IgE-independent mast cell degranulation in vitro and vivo.

The incidence of allergic diseases has increased to such a point that they have become common and have reached epidemic levels. However, their pathogenesis is not fully understood. Paeoniae Radix Rubra is a traditional Chinese medicine that is also used as a dietary supplement. Its main active ingredient is paeoniflorin. Paeoniflorin has good anti-inflammatory, immunomodulation, and antitumor effects. It is utilized in the treatment of various diseases in clinical settings. However, its effects on type I allergies and pseudoallergic reactions have not been comprehensively studied. In this study, we aimed to use DNP-IgE/DNP-BSA and C48/80 to simulate type I allergies and pseudoallergic reactions to evaluate the therapeutic effects of paeoniflorin to these diseases and identify its molecular mechanisms in cell degranulation both in vivo and in vitro. Results showed that paeoniflorin inhibited the degranulation of RBL-2H3 cells induced by these two stimuli (IgE-dependent and IgE-independent stimuli) in a dose-dependent manner. Moreover, qPCR and western blot analyses indicated that paeoniflorin may regulate the IgE/FcεR I, MRGPRB3, and downstream signal transduction pathways to exert its therapeutic effects on type I allergies and pseudoallergic reactions. In addition, DNP-IgE/DNP-BSA and compound 48/80 were used to induce the establishment of a passive cutaneous anaphylaxis mouse model. Paeoniflorin was found to suppress the extravasation of Evans Blue and tissue edema in the ears, back skin, and paws of the mice. This result further confirmed that paeoniflorin has a notable therapeutic effect on type I allergies and pseudoallergic reactions. Therefore, paeoniflorin could potentially be used as a drug for the treatment of type I allergies and pseudoallergic reactions. This study provides new insights into expanding the treatment range of paeoniflorin and its pharmacological mechanism.

Cisatracurium inhibits the growth and induces apoptosis of ovarian cancer cells by promoting lincRNA-p21

ABSTRACT As a common muscle relaxant, cisatracurium has shown good antitumor effect on some tumors. Recent studies reported that cisatracurium could inhibit the progression of colon cancer by upregulating tumor suppressor gene p53. However, its role in ovarian cancer and its regulatory effect on p53 and p53 downstream targeting gene long intergenic noncoding RNA p21 (lincRNA-p21) is still unknown. Quantitative Real-time Polymerase Chain Reaction (qRT-PCR) was used to assess the expression of p53, lincRNA-p21 and miR-181b. Cell viability and proliferation were detected by CCK-8 assay and Edu staining, respectively. Wound-healing and Transwell assays were performed to determine the abilities of cell migration and invasion. Apoptosis was evaluated by TUNEL staining. Luciferase reporter assay was conducted to detect the relationship between lincRNA-p21 and miR-181b. As a result, cisatracurium could increase the expressions of p53 and lincRNA-p21 of ovarian cancer cell line (OVCAR-3) in a dose-dependent manner. In addition, cisatracurium significantly inhibited the proliferation, migration and invasion of OVACR-3 cells, and induced apoptosis. However, these above changes in biological function can be attenuated by lincRNA-p21 knockdown. Next, lincRNA-p21 could directly target miR-181b and negatively regulate its expression by luciferase reporter assay. In conclusion, cisatracurium inhibited the progression of OVCAR-3 cells through upregulation of lincRNA-p21 expression activated by p53 inhibiting miR-181b expression. The experimental results provide a new research idea for the application of cisatracurium in ovarian cancer.