Human Hepatocellular Liver Carcinoma Cell Research Articles

Supramolecular combination chemotherapy: a pH-responsive co-encapsulation drug delivery system.

Most cancer chemotherapy regimens rely on the use of two or more chemotherapeutic agents. However, achieving the best possible dosing of the individual drugs can be challenging due to differences in metabolism, uptake, and clearance among other factors. Here we describe a supramolecular strategy for achieving drug delivery in which the loading ratio of two active components is easily defined. Specifically, we report the formation of aggregates comprised of self-assembled amphiphiles between carboxylatopillar[6]arene (CP6A) and an oxaliplatin (OX)-type Pt(iv) prodrug (PtC10). The association constant (K a) for the underlying host-guest interaction at pH 7.4 ((1.16 ± 0.03) × 104 M-1) is an order of magnitude higher than at pH 5.0 ((1.73 ± 0.15) × 103 M-1). A second chemotherapeutic, doxorubicin (DOX), may be encapsulated in the resulting vesicles (PtC10⊂CP6A) to give a supramolecular combination chemotherapeutic system DOX@PtC10⊂CP6A. Drug release studies served to confirm that PtC10 and DOX are released in acidic environments. Support for a synergistic antiproliferative effect relative to PtC10 + DOX came from cellular studies of DOX@PtC10⊂CP6A using the human liver hepatocellular carcinoma (HepG-2) cell line. In vivo studies revealed that DOX@PtC10⊂CP6A is not only able to retard tumor growth efficiently but also reduce drug-related toxic side effects in BALB/c nude mice bearing HepG-2 subcutaneous tumor xenografts. These favorable findings are attributed to the formation of a ternary complex that benefits from an enhanced permeability and retention (EPR) effect in vivo while allowing for the pH-based release of PtC10 and DOX at the tumor site.

Promising anti-cancer potency of 4,5,6,7-tetrahydrobenzo[d]thiazole-based Schiff-bases

Four new Schiff-bases have been synthesized from the 1:2 M condensation of 4,5,6,7-tetrahydrobenzothiazole-2,6-diamine with 2-hydroxybenzaldehyde (SL1), 5-Bromo-2-hydroxybenzaldehyde (SL2), 2-hydroxy-3-methoxybenzaldehyde (SL3) and 2-hydroxy-1-naphthaldehyde (SL4) and charactrised by UV–Vis, FT-IR, 1H NMR and mass spectroscopy. The crystal structures of SL1 and SL2 were determined by X-ray diffraction and the validity of gas-phase dft optimisations established by comparison with the diffraction data; by extension SL3 and SL4 were taken from dft computations.Molecular docking, circular dichroism and fluorescence quenching studies revealed one molecule of our Schiff-bases to bind to Human Serum Albumin (HSA). SL1 – SL4 are shown, by fluorescence quenching and circular dichroism, to present cytotoxic activity against the human breast-cancer (MCF-7) and the human hepatocellular liver-carcinoma (HepG2) cell lines in a concentration dependent manner: SL4 is the best in the series.

Mechanistic Insights into Oxidative Stress and Apoptosis Mediated by Tannic Acid in Human Liver Hepatocellular Carcinoma Cells.

The study investigated the cytotoxic effect of a natural polyphenolic compound Tannic acid (TA) on human liver hepatocellular carcinoma (HepG2) cells and elucidated the possible mechanisms that lead to apoptosis and oxidative stress HepG2 cell. The HepG2 cells were treated with TA for 24 h and various assays were conducted to determine whether TA could induce cell death and oxidative stress. The cell viability assay was used to determine the half maximal inhibitory concentration (IC50), caspase activity and cellular ATP were determined by luminometry. Microscopy was employed to determine deoxyribonucleic acid (DNA) integrity, while thiobarbituric acid (TBARS) and nitric oxide synthase (NOS) assays were used to elucidate cellular reactive oxygen species (ROS) and reactive nitrogen species (RNS), respectively. Western blotting was used to confirm protein expression. The results revealed that tannic acid induced caspase activation and increased the presence of cellular ROS and RNS, while downregulating antioxidant expression. Tannic acid also showed increased cell death and increased DNA fragmentation. In conclusion, TA was able to induce apoptosis by DNA fragmentation via caspase-dependent and caspase-independent mechanism. It was also able to induce oxidative stress, consequently contributing to cell death.

Harmicines − harmine and cinnamic acid hybrids as novel antiplasmodial hits

Harmicines constitute novel hybrid compounds that combine two agents with reported antiplasmodial properties, namely β-carboline harmine and a cinnamic acid derivative (CAD). Cu(I) catalyzed azide-alkyne cycloaddition was employed for the preparation of three classes of hybrid molecules: N-harmicines 6a-i, O-harmicines 7a-i and N,O-bis-harmicines 8a-g,i. In vitro antiplasmodial activities of harmicines against the erythrocytic stage of Plasmodium falciparum (chloroquine-sensitive Pf3D7 and chloroquine-resistant PfDd2 strains) and hepatic stage of P. berghei, as well as cytotoxicity against human liver hepatocellular carcinoma cell line (HepG2), were evaluated. Remarkably, most of the compounds exerted significant activities against both stages of the Plasmodium life cycle. The conjugation of various CADs to harmine resulted in the increased antiplasmodial activity relative to harmine. In general, O-harmicines 7 exhibited the highest activity against the erythrocytic stage of both P. falciparum strains, whereas N,O-bis harmicines 8 showed the most pronounced activity against P. berghei hepatic stages. For the latter compound, molecular dynamics simulations confirmed binding within the ATP binding site of PfHsp90, while the weaker binders, namely 6b and harmine, were found to be positioned away from this structural element. In addition, decomposition of the computed binding free energies into contributions from individual residues suggested guidelines for further derivatization of harmine towards more efficient compounds. Cytotoxicity screening revealed N-harmicines 6 as the least, and O-harmicines 7 as the most toxic compounds. Harmicines 6g, 8b and 6d exerted the most selective action towards Plasmodium over human cells, respectively. These results establish harmicines as hits for future optimisation and development of novel antiplasmodial agents.

Screening of antioxidant and cytotoxic activities of several microalgal extracts with pharmaceutical potential

The bioactive molecules from microalgae have important properties such as antioxidant, anticancer, antiviral, antibacterial, antihypertensive, skin regenerative, neuroprotective, sunscreen, and, immunostimulatory effects. Bioactive molecules derived from microalgae is getting intense attention from pharmaceuticals, cosmetics and nutraceuticals industries because of these properties and numerous researches have been done to investigate the role of these bioactive molecules that can enlighten microalgal biotechnology to result in new nature derived pharmaceutical formulations. In this study we investigate antioxidant activities of crude extracts of G. Galdieria sulphuraria, Ettlia carotinosa, Neochloris texensis, Chlorella minutissima, Stichococcus bacillaris, Schizochytrium limacinum, Crypthecodinium cohnii, and Chlorella vulgaris with determining radical scavenging activity (RSA) by DPPH (2,2-diphenyl-1-picrylhydrazyl hydrate radical) method and total phenolic content by Folin-Ciocalteu method. Selected extracts according to their antioxidant activities cytotoxicity was evaluated after exposure to human hepatocellular liver carcinoma cells (HepG2) for 48 h. Antioxidant activities of these species ranged from 89 to 95% RSA (radical scavenging activity) while their phenolic contents were also very high, varied from 41 to 312 mg GAE (gallic acid equivalents)/mg extract. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay also showed microalgae has a potential to be used as a novel therapeutic compound.

Syntheses, crystal structure and biological evaluation of three novel Cu (II) complexes with Schiff base derived from fluorinated amino acid and Salicylaldehyde

Three novel Cu (II) coordination complexes, formulated as [Cu3(C14H8NO3F)2(CH3COO)2]n (1), [Cu2(C14H9NO3F)2(CH3COO)Cl] (2) and [Cu(C14H8NO3F)(CH3OH)2] (3), have been synthesized by 3‐Fluoroanthranilic acid, Salicylaldehyde and Cu (II) salt as sources in different reaction conditions and characterized by single crystal X‐ray diffraction, X‐ray powder diffraction, IR spectroscopy and elemental analysis. Single‐crystal diffraction analysis revealed that the complexes exhibited different coordination modes and conformations which were linked into multidimensional networks through some weak interactions. The biological activities vary greatly on account of the different Cu (II) numbers among the three complexes. In order to discuss the bioactivities, the complexes have been screened for antimicrobial activities against E. coli and S. aureus, antitumor activities against A549 (human lung cancer cells), Hela (human cervical cancer cells) and HepG‐2(human liver hepatocellular carcinoma cells). Their interactions with calf thymus DNA were investigated by UV–visible and fluorescence spectrometry, as well as viscosity measurements. Interestingly, 1 (the rare 3‐core Cu (II) coordination polymer) shows great antibacterial activities and highest DNA binding affinities. Antitumor studies revealed that complex 1 also exhibited highest activity.

HOTAIR regulates lipopolysaccharide-induced inflammatory response in hepatocytes.

It has been widely accepted that long-noncoding RNA (lncRNA) HOX transcript antisense intergenic RNA (HOTAIR) emerges as a crucial mediator in inflammation. Here, we first detected HOTAIR in lipopolysaccharide (LPS)-treated normal human liver cell line (L02) and hepatocellular carcinoma cell lines (C3A, HepG2, and SMMC-7721). Further, we explored the biological function of HOTAIR in LPS-induced hepatocytes (L02 and C3A) lesions and investigated the molecular mechanisms. Besides, we focused on inflammatory signaling crosstalk. The inflammatory insults were assayed by cell counting kit-8 (CCK-8), cell cycle and apoptosis analysis kit, and immunoblotting assay. HOTAIR level was examined by reverse-transcription polymerase chain reaction. To determine the effect of HOTAIR silence or overexpression in inflammation, we applied quantitative reverse-transcription polymerase chain reaction, immunoblotting assay, and enzyme-linked immuno sorbent assay. Regulator inhibitors of Janus kinase/signal transducer and activator of transcription (JAK2/STAT3; AG490) and nuclear factor κB (NF-κB; BAY-11-7082) were applied to treat cells. Our results suggested that LPS induced the overexpression of HOTAIR in L02, C3A, HepG2, and SMMC-7721 cells. LPS repressed viability, induced apoptosis, and facilitated the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in L02 and C3A cells. IL-1β, IL-6, and TNF-α were upregulated by HOTAIR overexpression while downregulated by HOTAIR knockdown in LPS-treated cells. We further observed that HOTAIR overexpression accelerated LPS-induced phosphorylation whereas HOTAIR silence blocked this progress. Inhibition of JAK/STAT and NF-κB contributed to the suppression of cytokines which was evoked by LPS. Collectively, our findings indicated that HOTAIR exerted a crucial role in cytokines expression by activating JAK/STAT and NF-κB.

Transition Metal Complexes of (E)‐2((2‐hydroxybenzylidene) amino‐3‐mercaptopropanoic acid: XRD, Anticancer, Molecular modeling and Molecular Docking Studies

AbstractThe anticancer studies of a Schiff base; (E)‐2((2‐hydroxybenzylidene)amino‐3‐mercaptopropanoic acid (H2L) (obtained from 2‐hydroxybenzaldehyde and L‐cysteine) and its transition metal complexes have been reported. The evaluation of the growth inhibitory action was studied for the compounds against human colon carcinoma (HCT‐116), human hepatocellular liver carcinoma (HEPG‐2), normal melanocytes (HFB‐4) and human breast carcinoma (MCF‐7) cell lines. The obtained results revealed that the Schiff base and its chelates are active against human hepatocellular liver carcinoma (HEPG‐2) cell lines. The powder X‐ray diffraction analysis for the compounds was carried out through Phillips X′Pert High score software. The density functional theory computation for ligand and Co(II), Ni(II) and Cu(II) metal complexes were made to understand the mode of bonding by GAUSSIAN 03 rev. A.01 programme. The quantitative structure‐activity relationship investigation was performed by using HyperChem Professional 8.0.3 software to understand the biological potency of the ligands. Moreover, a docking analysis using iGEMDOCKv2.1 software was carried out against the kinase enzyme PDB ID:1fvv.

Catechins Controlled Bioavailability of Benzo[a]pyrene (B[α]P) from the Gastrointestinal Tract to the Brain towards Reducing Brain Toxicity Using the In Vitro Bio-Mimic System Coupled with Sequential Co-Cultures.

The aim of the current study was to examine the preventive effect of green tea catechins on the transport of Benzo[a]pyrene (B[α]P) into the brain using an in vitro bio-mimic system coupled with sequential co-cultures. When 72 μM of catechins was pre-treated, cellular cytotoxicity induced by IC50 of B[α]P in human liver hepatocellular carcinoma (HepG2) and human brain microvascular endothelial cells (HBMECs) was reduced by 27% and 26%, respectively. The cellular integrity measured in HBMECs, which was exposed to IC50 of B[α]P, slowly decreased. However, the pre-treatment of catechins retained cellular integrity that was 1.14 times higher than with the absence of catechins. Co-consumption of catechins reduced not only the bio-accessibility of B[α]P in digestive fluid, but it also decreased absorption of B[α]P in human intestinal epithelial cells (Caco-2) with a HepG2 co-culture system. It was found that approximately a two times lower amount of B[α]P was transported via the blood-brain barrier (BBB) compared to only the B[α]P intake. These results are taken in conjunction with each other support that catechins could be able to prevent brain toxicity induced by B[α]P in the human body by limiting the bio-availability of B[α]P.

Chemical Characterization of Two Seasonal PM2.5 Samples in Nanjing and Its Toxicological Properties in Three Human Cell Lines

PM2.5 pollution is of great concern in China due to its adverse health effects. Many diseases have been proven to be associated with PM2.5 components, but the effects of chemical characteristics of PM2.5 on toxicological properties, especially in different human organs, are poorly understood. In this study, two seasonal PM2.5 samples (summer and winter) were collected in Nanjing, and their chemical compositions (heavy metals, water-soluble ions, organic carbon (OC), and elemental carbon (EC)) were analyzed. Human lung epithelial carcinoma cells (A549), human hepatocellular liver carcinoma cells (HepG2), and human neuroblastoma cells (Sh-Sy5y) were employed to evaluate the toxicological properties of the collected PM2.5. The results showed that the average mass concentrations of PM2.5 were lower in summer (51.3 ± 21.4 μg/m3) than those in winter (62.1 ± 21.5 μg/m3). However, the mass fractions of heavy metals, OC, and EC exhibited an opposite seasonal difference. Among all tested fractions, water-soluble ions were the major compositions of particles in both summer and winter, especially the secondary ions (SO42−, NO3− and NH4+). Besides, the ratio of OC/EC in PM2.5 was greater than two, indicating serious secondary pollution in this area. The NO3–/SO42− ratio (< 1) suggested that fixed sources made important contributions. The toxicological results showed that PM2.5 in the summer and winter significantly inhibited cell viability (p < 0.01) and induced intracellular reactive oxygen species (ROS) production (p < 0.01). Moreover, the viability inhibition in A549, Sh-Sy5y, and HepG2 cells was more prominent in summer, especially at high PM2.5 (400 μg/mL) (p < 0.05), and the induction of reactive oxygen species (ROS) in A549 and Sh-Sy5y cells was also more evident in summer. Such seasonal differences might be related to the variations of PM2.5 components.

Functionalized docetaxel-loaded lipid-based-nanosuspensions to enhance antitumor efficacy in vivo.

Purpose: To further enhance the antitumor efficacy through targeted delivery, DTX loaded lipid-based-nanosuspensions (DTX-LNS) were prepared and functionalized by PEGylation or NGR modification to develop DSPE-PEG2000 modified DTX-LNS (P-DTX-LNS) or DSPE-PEG2000-NGR modified DTX-LNS (N-DTX-LNS), respectively.Methods: Based on our previous work, functionalized DTX-LNS including P-DTX-LNS and N-DTX-LNS were prepared using thin-film hydration, and then characterized. Release behavior, stability in vitro, cytotoxicity and cellular uptake of functionalized LNS were observed. To demonstrate tumor targeting efficiency of functionalized DTX-LNS, in vivo real-time and ex vivo imaging study were conducted. Furthermore, therapeutic efficacy in vivo was evaluated in an H22-bearing mice model.Results: Functionalized DTX-LNS 100–110 nm in diameter were successfully prepared and exhibited good stability under various conditions. In vitro release studies demonstrated that DTX was released from functionalized DTX-LNS steadily and reached approximately 95% at 48 hrs. Functionalized DTX-LNS showed dose-dependent cytotoxicity and time-dependent internalization in human hepatocellular liver carcinoma cells (HepG2) cells. In vivo real-time and ex vivo imaging results indicated that tumor targeting efficiencies of P-DiR-LNS and N-DiR-LNS were 29.9% and 34.3%, respectively. Moreover, evaluations of in vivo antitumor efficacy indicated that functionalized DTX-LNS effectively inhibited tumor growth with low toxicity.Conclusion: The functionalized LNS exhibited suitable particle size, nearly spherical structure, enough drug loading and great potentials for large-scale production. The results in vitro and in vivo demonstrated that functionalized LNS could realize tumor targeting and antitumor efficacy. Consequently, functionalized DTX-LNS could be expected to be used for tumor targeting therapy.

A quick accelerating microwave-assisted sustainable technique: permutated spiro-casing for imaging experiment.

A quick access tool for the one-pot, chromatography-free synthesis of the diversified dihydrospiro[indeno[1,2-b]pyridine-4,3'-indoline or acenaphthylene-1,4'-indeno[1,2-b]pyridine spiro-analogous via sustainable microwave condition in minimal 1:1 (v/v) aqueous ethanol without any metal catalyst is demonstrated here. This permutated spiro-casing was designed as fluorescence probe at physiological pH for selective detection of Zn2+, even in the presence of other competitive ions and showed a fluorescent enhancement with 1:1 metal/ligand complex. Moreover, this spiro sensor was successfully applied as an effective intracellular Zn2+ imaging agent in the biomedical study of human hepatocellular liver carcinoma cells (HepG2) due to its cell permeability property. A quick access technique for the permutated dihydrospiro-pyridine via chromatography-free sustainable microwave condition and its applications as organic fluorescence probe at physiological pH for selective detection of Zn2+ and effective intracellular Zn2+ imaging in HepG2 cells.

Cell Imaging Using Two-Photon Excited CdS Fluorescent Quantum Dots Working within the Biological Window.

In recent years, two-photon excited semiconductor quantum dots (QDs) have been the subject of intense investigation due to their long excitation wavelength which helps to achieve deeper penetration and higher image resolution in optical bioimaging. In this paper, water-soluble CdS QDs were synthesized using a hydrothermal method and applied to human liver hepatocellular carcinoma (HepG2) cells. The first-principles calculation suggested that the S-rich defected structure contributes to a narrower band gap compared to the pristine structure. The resulting fluorescence wavelength was significantly red shifted, which was attributed to the deep defect states emission. The large Stokes shifts (> 200 nm) of the QDs can eliminate the possible cross-talk between the excitation light and the emission light. Two-photon induced red fluorescence emission can avoid overlapping with the autofluorescence emission of biological samples. The uptake and cell viability measurements of the HepG2 cells showed a good biocompatibility and a low toxicity of CdS QDs. Two-photon excited scanning microscopy images revealed that the HepG2 cells incubated with CdS QDs emitted bright red upconversion fluorescence and the fluorescence brightness was 38.2 times of that of the control group. These results support CdS QDs as a good candidate for application in cellular imaging.

Anticancer Effects and Cell Death Pathways in Ultralow-Power 980 nm Laser-Triggered Photodynamic Therapy by Gd₂O₃:Yb, Tm Nanoparticles.

Upconverting Gd₂O₃:Yb, Tm nanoparticles that can provide photodynamic therapy (PDT) for cancer cells upon 980 nm near-infrared (NIR) laser irradiation are prepared. The nanoparticles emit bright blue upconversion fluorescence (470∼520 nm) when excited by a 980 nm laser. A well-selected PDT drug, merocyanine 540 (MC540), which shows an absorption maximum within the 495∼540 nm band, is loaded onto the surface of the nanoparticles to obtain Gd₂O₃:Yb, TmMC540. A prominent PDT-induced killing effect on both human cervical cancer cells (HeLa cells) and human hepatocellular liver carcinoma cells (HepG2 cells) is achieved under 980 nm laser irradiation at a very low power density of 0.65 W cm-2, which is lower than The American National Standard for the safe use of 980 nm lasers (0.72 W cm-2. The cell death modes are further studied in detail via a uranyl acetate section-staining method to analyze the morphological cell changes before and after PDT. With clear evidence of mitochondrial damage, chromatin condensation and the formation of apoptotic bodies, an apoptosis mechanism is confirmed to be responsible for both HeLa and HepG2 cell death in Gd₂O₃:Yb, Tm-MC540-mediated PDT. Due to excessive damage, the cancer cells are efficiently killed, and autophagy is found to be initiated immediately after PDT.

Cytotoxic Alkaloids from Leaves of Pilea aff. martinii.

Two new phenanthroquinolizidine alkaloids (1: and 2: ) and a new piperidine derivative (3: ) were isolated from the leaves of Pilea aff. martinii together with 3 known alkaloids: julandine (4: ), cryptopleurine (5: ), and 1,3,6,6-tetramethyl-5,6,7,8-tetrahydro-isoquinolin-8-one (6: ). Their structures were determined by spectral data analyses including mass spectrometry and 2-dimensional nuclear magnetic resonance data. The absolute configurations of 1: -3: were established by comparison of their experimental circular dichroism data with the calculated electronic circular dichroism spectra. The isolated compounds were evaluated for their cytotoxicity against 4 cancer cell lines: KB (mouth epidermal carcinoma cells), HepG-2 (human liver hepatocellular carcinoma cells), LU-1 (human lung adenocarcinoma cells), and MCF-7 (human breast cancer cells). The new phenanthroquinolizidine pileamartine D (2: ) showed strong and selective proliferation inhibition toward KB and HepG-2 cells with IC50 values of 25 and 27 nM, respectively. Pileamartine C (1: ), julandine (4: ), and cryptopleurine (5: ) exhibited cytotoxicity against 4 tested cancer cell lines with IC50 values less than 1 µM.

Synthesis of novel chalcones through palladium-catalyzed C[sbnd]O cross-coupling reaction of bromo-chalcones with ethyl acetohydroxamate and their antiplasmodial evaluation against Plasmodium falcipuram in vitro

An efficient method for palladium-catalyzed CO cross-coupling of ethyl acetohydroxamate (EAcHO) with 4-bromo-chalcones has been developed to synthesize novel chalcones. The two supporting ligands, namely tBuXPhos (L7), and cataCXium®PIntB (L16) were found to be effective ligands towards the Pd-catalyzed CO cross-coupling reaction to afford the desired product in moderate to excellent yields (50–99%). The coupled products were screened for in vitro blood stage antiplasmodial activity against Plasmodium falciparum (3D7) using the [3H] hypoxanthine incorporation inhibition assay. Of the twenty two compounds screened, eleven showed good antiplasmodial activity with IC50 values ranging from 6–16 μg/mL. The selected active molecules 11, 16, 22, (IC50 12 μg/mL) and 19 (IC50 6 μg/mL) were studied for their cytotoxic effect against HepG2 Cells (human hepatocellular liver carcinoma cell lines), showing the selectivity index (SI) values are greater than 4 except chalcone 22. Our result demonstrates a methodology for synthesizing novel chalcones as a new class of antiplasmodial agent.

Illuminating the Anticancerous Efficacy of a New Fungal Chassis for Silver Nanoparticle Synthesis.

Biogenic silver nanoparticles (Ag NPs) have supple platforms designed for biomedical and therapeutic intervention. Utilization of Ag NPs are preferred in the field of biomedicines and material science research because of their antioxidant, antimicrobial, and anticancerous activity along with their eco-friendly, biocompatible, and cost-effective nature. Here we present a novel fungus Piriformospora indica as an excellent source for obtaining facile and reliable Ag NPs with a high degree of consistent morphology. We demonstrated their cytotoxic property, coupled with their intrinsic characteristic that make these biogenic nanoparticles suitable for the anticancerous activity. In vitro cytotoxicity of biologically synthesized Ag NPs (BSNPs) and chemically synthesized Ag NPs (SNPs) was screened on various cancer cell lines, such as Human breast adenocarcinoma (MCF-7), Human cervical carcinoma (HeLa), Human liver hepatocellular carcinoma (HepG2) cell lines and embryonic kidney cell line (HEK-293) as normal cell lines. The antiproliferative outcome revealed that the BSNPs exhibited significant cytotoxic activity against MCF-7 followed by HeLa and HepG2 cell lines as compared to SNPs. The blend of cytotoxic properties, together with green and cost-effective characteristics make up these biogenic nanoparticles for their potential applications in cancer nanomedicine and fabrication coating of ambulatory and non-ambulatory medical devices.

The effect of CTCF binding sites destruction by CRISPR/Cas9 on transcription of metallothionein gene family in liver hepatocellular carcinoma

Chromatin spatial organization is essential for transcriptional modulation and stabilization. The pattern of DNA distal interplay form the multiple topological associating domains (TADs), and further assemble the functional compartmentalization with open and expression-active chromatin ("A" compartments) or closed and expression-inactive chromatin ("B" compartments) in genome, whose boundaries were defined by the high enrichment of CCCTC-binding factor (CTCF). Nevertheless, As a potential therapeutic strategy, changing the local chromatin architecture via adding or removing the CTCF binding sites in situ to regulate the transcription activity of genes within one TAD in cancer cells is poorly explored. In present study, we observed that the metallothionein (MT) family were all remarkably decreased in HCC of TCGA database, and MT genes family were located within a TAD of 1.2 Mb at 16q13 in order, and CTCF binding sites were distributed at the both sites of MT gene clusters. Furthermore, CRISPR/Cas9 was employed to destroy the CTCF binding sites at the vicinity of the MT family in human liver hepatocellular carcinoma (HCC) cell lines Huh-7 and HepG2. And the presence of up-regulated transcription of MTs were observed in Huh-7 and HepG2 cells compared to normal liver CRL-12461 cells. Moreover, the presence of the varying DNA interplay as well as H3K4me3 and H3K9me3 modification on different MT genes were observed after CTCF binding domain destruction compared to the control using chromosome conformation capture (3C) and chromatin immunoprecipitation (ChIP). Our results determined a potential way to regulate the transcription of a series of genes via changing the local genomic organization for diseases treatment.

A Microwave-Enhanced Synthesis and Biological Evaluation of N-Aryl‑5,6,7,8‑tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amines

A series of N-aryl-5,6,7,8-tetra-hydrobenzo[4,5]thieno[2,3-d ]pyrimidin-4-amines were synthesized in moderate to good yield by using a microwave-enhanced conditions. The selected compounds were evaluated for their cytotoxic effects (IC50 values) on human pulmonary carcinoma (A549), murine BALB/c spontaneous colon adenocarcinoma (CT26) and human hepatocellular liver carcinoma (HepG2) cell lines in vitro. Amongst these compounds, one compound was found to have the better cytotoxic activity with reference to the standard Erlotinib hydrochloride (Tarceva™) against A549 (IC50 = 16.06 ± 0.09 µM) and HepG2 (IC50 = 15.01 ± 0.31 µM) cell lines. Especially, two compounds showed best cytotoxic effects against CT26 (IC50 = 11.38 ± 0.44 µM) and HepG2 (IC50 = 8.51 ± 0.52 µM) cell lines, respectively. The preliminary structure-activity relationships were disclosed and the thieno[2,3-d] pyrimidine skeleton could be exploited to potential antitumor agents in the future.

Synthesis and bioevaluation of novel steroidal isatin conjugates derived from epiandrosterone/androsterone

Steroids are classes of natural products widely distributed in nature, which have been demonstrated to exhibit broad biological functions, and have also attracted increasing interest from bioorganic and pharmaceutical researches. In order to develop novel chemical entities as potential cytotoxic agents, a series of steroidal isatin conjugations derived from epiandrosterone and androsterone were efficiently prepared and characterized, and all these obtained compounds were screened for their potential cytotoxic activities. The preliminary bioassay indicated that most of the newly synthesized compounds exhibited good cytotoxic activities against human gastric cancer (SGC-7901), melanoma (A875), and hepatocellular liver carcinoma (HepG2) cell lines compared with 5-fluorouracil (5-FU), which might be considered as promising scaffold for further development of potential anticancer agents.