Polyaniline-Modified Oriented Graphene Hydrogel Film as the Free-Standing Electrode for Flexible Solid-State Supercapacitors

In this study, we report polyaniline (PANI)-modified oriented graphene hydrogel (OGH) films as the free-standing electrode for flexible solid-state supercapacitors (SCs). The OGH films are prepared by a facile filtration method using chemically converted graphene sheets and then introduced to PANI on the surface of OGH films by in situ chemical polymerization. The PANI-modified OGH films possess high flexibility, high electrical conductivity, and mechanical robustness. The flexible solid-state SCs based on the PANI-modified OGH films exhibit a specific capacitance of 530 F/g, keeping 80% of its original value up to 10 000 charge–discharge cycles at the current density of 10 A/g. Remarkably, the flexible solid-state SCs maintain ∼100% capacitance retention bent at 180° for 250 cycles. Moreover, the flexible solid-state SCs are further demonstrated to be able to light up a red-light-emitting diode. These results indicate that the flexible solid-state SCs based on PANI-modified OGH films as the free-standing electrode have potential applications as energy-storage devices

Enhanced Thermoelectric Properties of Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) by Binary Secondary Dopants

To simultaneously increase the electrical conductivity and Seebeck coefficient of poly­(3,4-ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS) was a challenge for realizing efficient organic thermoelectrics. In this study, for the first time, we report both increased electrical conductivities and Seebeck coefficients, hence, enhanced thermoelectric properties of PEDOT:PSS thin films by doped with binary secondary dopants, dimethyl sulfoxide (DMSO) and poly­(ethylene oxide) (PEO). Without modifying film morphology, the molar ratios of PEDOT to PSS are tuned by PEO, resulting in increased proportions of PEDOT in the bipolaron states. Our study provides a facile route to optimizing thermoelectric properties of PEDOT:PSS thin films

Concomitant Targeting of Multiple Key Transcription Factors Effectively Disrupts Cancer Stem Cells Enriched in Side Population of Human Pancreatic Cancer Cells

<div><p>Background</p><p>A major challenge in the treatment of pancreatic ductal adenocarcinoma is the failure of chemotherapy, which is likely due to the presence of the cancer stem cells (CSCs).</p> <p>Objective</p><p>To identify side population (SP) cells and characterize s-like properties in human pancreatic cancer cell lines (h-PCCLs) and to exploit the efficacy of concomitant targeting of multiple key transcription factors governing the stemness of pancreatic CSCs in suppressing CSC-like phenotypes.</p> <p>Methods</p><p>Flow cytometry and Hoechst 33342 DNA-binding dye efflux assay were used to sort SP and non-SP (NSP) cells from three h-PCCLs: PANC-1, SW1990, and BxPc-3. The self-renewal ability, invasiveness, migration and drug resistance of SP cells were evaluated. Expression of CSC marker genes was analyzed. Tumorigenicity was assessed using a xenograft model in nude mice. Effects of a complex decoy oligonucleotide (cdODN-SCO) designed to simultaneously targeting Sox2, Oct4 and c-Myc were assessed.</p> <p>Results</p><p>CSCs were enriched in the side proportion (SP) cells contained in the h-PCCLs and they possessed aggressive growth, invasion, migration and drug-resistance properties, compared with NSP cells. SP cells overexpressed stem cell markers CD133 and ALDH1, pluripotency maintaining factors Nanog, Sox2 and Oct4, oncogenic transcription factor c-Myc, signaling molecule Notch1, and drug resistant gene ABCG2. Moreover, SP cells consistently demonstrated significantly greater tumorigenicity than NSP cells in xenograft model of nude mice. CdODN–SOC efficiently suppressed all CSC properties and phenotypes, and minimized the tumorigenic capability of the SP cells and the resistance to chemotherapy. By comparison, the negative control failed to do so.</p> <p>Conclusion</p><p>The findings indicate that targeting the key genes conferring the stemness of CSCs can efficiently eliminate CSC-like phenotypes, and thus may be considered a new approach for cancer therapy. Specifically, the present study establishes the combination of Sox2/Oct4/c-Myc targeting as a potential anti-pancreatic cancer agent worthy of further studies in preclinical settings.</p> </div

Enhanced <i>in vivo</i> tumorigenicity of SP cells and the anti-tumor effects of cdODN-SOC in BALB/C nude mice.

<p>PANC-1 SP and NSP cells were orthotopically inoculated s.c. to the left dorsal flank of mice. On 50 days after inoculation, the mice were sacrificed to detect tumor formation. (<b>A</b>) The SP cells regenerated larger tumors than corresponding NSP cells at every cell dose. ***p<0.001 SP vs NSP; n=6. (B) Representative images of tumors in nude mice showing the difference in the tumorigenic potentials between SP and NSP and the anti-tumor effects of cdODN-SOC, as well as the drug resistance of SP-induced tumor to gemcitabine. For the PANC-1 cell line, as few as 1×104 SP cells formed tumors, while 1×106 NSP cells were required to initiate a tumor. (C) Mean data of tumor volume under different conditions. Note the ability of cdODN-SOC to reduce the tumor volume. ***p<0.001 vs SP; n=6.</p

Enhanced drug resistance of SP cells and suppression by cdODN-SOC.

<p>(<b>A</b>) Percent cell survival measured by MTT assay in PANC-1 CSCs. All cells were all treated with varying concentrations of gemcitabine and with lipofectamine 2000. Symbols are experimental data and the lines represent best fits to Hill equation. ***p<0.001 vs SP alone for comparison of IC50 values; n=4. (B) Percent apoptotic cells measured by ELISA to quantify DNA fragmentation in PANC-1 CSCs. All cells were all treated with varying concentrations of gemcitabine and with lipofectamine 2000. Symbols are experimental data and the lines represent best fits to Hill equation. ***p<0.001 vs SP alone for comparison of IC50 values; n=4. Quantitatively the same results were obtained from SW1990 and BxPc-3 CSCs (data not shown).</p

Analysis of the side population (SP) in three human pancreatic cancer cell lines PANC-1, SW1990, and BxPc-3, using flow cytometry and Hoechst33342 dye.

<p>(<b>A</b>) Examples of floe cytometry analysis of SP cells in the presence or absence of 30 µM verapamil, cdODN-SOC (a complex decoy oligodeoxynucleotide carrying <i>cis</i>-elements for Sox2, Oct4 and c-Myc), or NC–ODN (negative control cdODN). (<b>B</b>) The SP proportions as percentage of total population. ***<i>p</i><0.001 <i>vs</i> Control; n=4.</p

Inhibition of SP cell invasion and migration by cdODN-SOC.

<p>(<b>A</b>) Invasion assay. PANC-1 CSCs were plated onto the Matrigel-coated membrane in the top chamber of the transwell and transfected or treated with gemcitabine for 48 h. All cells were mock-treated with lipofectamine 2000. Cells invaded to the lower chambered were fixed with methanol, stained with crystal violet and counted. ***p<0.001 vs SP alone; n=6. (B) Migration assay. PANC-1 CSCs were plated in the top chamber of the transwell and transfected or treated with gemcitabine for 36 h. All cells were mock-treated with lipofectamine 2000. Cells migrated to the lower chambered were fixed with methanol, stained with crystal violet and counted. ***p<0.001 vs SP alone; n=5. Quantitatively the same results were obtained from SW1990 and BxPc-3 CSCs (data not shown).</p

Validation of the ability of cdODN-SOC to bind target transcription factors, assessed by electrophoretic mobility shift assay (EMSA).

<p>(<b>A</b>) The sequences of the cdODN-SOC carrying <i>cis</i>-elements for Sox2, Oct4 and c-Myc and the negative control ODN with nucleotide replacements (NC–ODN). (<b>B</b>) Examples of EMSA images showing the ability of cdODN-SOC to bind human recombinant Sox2, Oct4 or c-Myc protein. The shift bands indicate the positions of the DNA-protein complexes and the supershift bands indicate the specific DNA-protein binding picked up by the respective antibody. Lane labels: 1, control with no proteins; 2: in the presence of cold or unlabeled cdODN-SOC; 3: in the presence of cdODN-SOC; 4: in the presence of NC–ODN; and 5: with antibody.</p

Deciphering Nonbioavailable Substructures Improves the Bioavailability of Antidepressants by Serotonin Transporter

Inadequate bioavailability is one of the most critical reasons for the failure of oral drug development. However, the way that substructures affect bioavailability remains largely unknown. Serotonin transporter (SERT) inhibitors are first-line drugs for major depression disorder, and improving their bioavailability may be able to decrease side-effects by reducing daily dose. Thus, it is an excellent model to probe the relationship between substructures and bioavailability. Here, we proposed the concept of “nonbioavailable substructures”, referring to substructures that are unfavorable to bioavailability. A machine learning model was developed to identify nonbioavailable substructures based on their molecular properties and shows the accuracy of 83.5%. A more potent SERT inhibitor DH4 was discovered with a bioavailability of 83.28% in rats by replacing the nonbioavailable substructure of approved drug vilazodone. DH4 exhibits promising anti-depression efficacy in animal experiments. The concept of nonbioavailable substructures may open up a new venue for the improvement of drug bioavailability

Deciphering Nonbioavailable Substructures Improves the Bioavailability of Antidepressants by Serotonin Transporter

Inadequate bioavailability is one of the most critical reasons for the failure of oral drug development. However, the way that substructures affect bioavailability remains largely unknown. Serotonin transporter (SERT) inhibitors are first-line drugs for major depression disorder, and improving their bioavailability may be able to decrease side-effects by reducing daily dose. Thus, it is an excellent model to probe the relationship between substructures and bioavailability. Here, we proposed the concept of “nonbioavailable substructures”, referring to substructures that are unfavorable to bioavailability. A machine learning model was developed to identify nonbioavailable substructures based on their molecular properties and shows the accuracy of 83.5%. A more potent SERT inhibitor DH4 was discovered with a bioavailability of 83.28% in rats by replacing the nonbioavailable substructure of approved drug vilazodone. DH4 exhibits promising anti-depression efficacy in animal experiments. The concept of nonbioavailable substructures may open up a new venue for the improvement of drug bioavailability