Search

The full-length AU-rich (63.14%) 2,794-nucleotide sequence of Rhizoctonia mitovirus K1 (RMV-K1) isolated from the binucleate AG-K strain FAS2909W was determined. The positive strand of RMV-K1 contains a large open reading frame (ORF) when the fungal mitochondrial genetic code is used. This ORF was predicted to encode an RdRp protein exhibiting the highest sequence identity (41.77%) to Rhizoctonia solani mitovirus 30. Phylogenetic analysis showed that RMV-K1 is a novel member of the genus Mitovirus, family Mitoviridae. [ABSTRACT FROM AUTHOR]

We report the development of a small interfering RNA (siRNA) delivery vector based on cationic perfluorocarbon nanoemulsions. We have prepared perfluorodecalin (PFD) emulsions with a positive surface charge provided by a fluorinated poly(ethylenimine) (F-PEI). The fluorinated emulsion (F-PEI@PFD) reduced cytotoxicity of F-PEI and demonstrated effective binding with siRNAs to form nanosized emulsion polyplexes. The prepared emulsion polyplexes enhanced cellular uptake and improved endosomal escape of the siRNA. In addition to increased reporter gene silencing in multiple cancer cell lines, when compared with control F-PEI and PEI polyplexes, the siRNA emulsion polyplexes showed an excellent resistance to serum deactivation and maintained high activity, even in high-serum conditions. The F-PEI@PFD emulsion polyplexes carrying an siRNA to silence the expression of Bcl2 gene induced apoptosis and inhibited tumor growth in a melanoma mouse model in vivo and showed potential for in vivo ultrasound imaging. This study demonstrates the potential of F-PEI@PFD emulsions as a multifunctional theranostic nanoplatform for safe siRNA delivery, with integrated ultrasound imaging functionality. [ABSTRACT FROM AUTHOR]

Purpose: We describe here a novel lyophilized nanosuspension technology in order to improve the dissolution rate and oral bioavailability of the insoluble drug P2X7 receptor antagonist (PRA), which is an effective antagonist to P2X7 receptor for non-steroidal anti-inflammatory. Methods: PRA-lyophilized nanosuspension (PRA-LNS) was fabricated by anti-solvent precipitation in combination with high pressure homogenization, and then lyophilized for prolonged storage. After preparations, various characterization experiments were performed including particle size, zeta potential, surface morphology, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), in vitro dissolution study, and in vivo pharmacokinetic study. Results: The re-dissolved particle size of PRA-LNS was about 180~250 nm with uniform distribution, confirmed by TEM image. The drug PRA in nanosuspensions possessed crystalline form evaluated via XRPD and DSC analysis. The solubility of PRA-LNS in water was 1.52 times larger than PRA raw drug; in vitro dissolution tests showed that PRA-LNS could dissolve completely within 5 min, which is a significant improvement compared to the raw drug. The relative bioavailability of PRA-LNS is 290.70% compared to the raw drug and 177.94% compared to the physical mixture. Conclusions: PRA-LNS could easily re-disperse in water with increased solubility, enhanced oral bioavailability, and controllable production process. [ABSTRACT FROM AUTHOR]

Most therapeutic proteins are classified as class III drugs according to the Biopharmaceutical Classification System means that the low permeability across the intestinal epithelium is the rate-limited step for their oral absorption. Cationic chitosan nanoparticles have been found to open the tight junctions between epithelial cells. On the other hand, bioadhesive delivery devices could prolong the gastrointestinal residence time. In the present study, we developed a novel nano-reservoir bioadhesive tablets that combining the advantages of cationic nanoparticles and bioadhesive delivery devices anticipated achieving effective transport of sufficient protein drugs across the intestinal epithelium. The nano-reservoir in bioadhesive tablets was composed of chitosan nanoparticles (CS-NPs) loading a model protein drug bovine serum albumin (BSA). The formula of bioadhesive tablets was optimized by using rotatable central composite design and response surface methodology. The nano-reservoir, BSA-loaded CS-NPs, had an average particle diameter of 312.5 ± 12.89 nm and zeta-potential value of 26.76 ± 3.56 mV. Carboxymethyl chitosan added to the formula significantly ameliorated the tight junction damage of the Caco-2 cell monolayer induced by CS-NPs, meanwhile maintained the high transport efficiency of BSA. Permeability study exhibited that these nano-reservoir bioadhesive tablets combining the advantages of cationic nanoparticles and bioadhesive tablets significantly enhanced BSA transport through rabbit small intestine in comparison with either conventional bioadhesive tablets or CS-NPs. Therefore, these nano-reservoir bioadhesive tablets provided a great potential dosage form design for the oral delivery of protein drugs. [ABSTRACT FROM AUTHOR]

AJS is the code name of an untitled novel medicative compound synthesized by the Tasly Holding Group Company (Tianjin, China) based on the structure of cinnamamide, which is one of the Biopharmaceutics Classification System (BCS) class II drugs. The drug has better antidepressant effect, achieved by acting on the 5-hydroxytryptamine receptor. However, the therapeutic effects of the drug are compromised due to its poor water solubility and lower bioavailability. Herein, a self-microemulsifying drug delivery system (SMEDDS) was developed to improve its solubility and oral bioavailability. AJS-SMEDDS formulation was optimized in terms of drug solubility in the excipients, droplet size, stability, and drug precipitation using a pseudo-ternary diagram. The pharmacokinetic study was performed in rats, and the drug concentration in plasma samples was assayed using the high-performance liquid chromatography-electrospray tandem mass spectrometry (HPLC-MS/MS) method. The optimized formulation for SMEDDS has a composition of castor oil 24.5%, Labrasol 28.6%, Cremphor EL 40.8%, and Transcutol HP 2.7% (co-surfactant). No drug precipitation or phase separation was observed from the optimized formulation after 3 months of storing at 25°C. The droplet size of microemulsion formed by the optimized formulation was 26.08 ± 1.68 nm, and the zeta potential was −2.76 mV. The oral bioavailability of AJS-SMEDDS was increased by 3.4- and 35.9-fold, respectively, compared with the solid dispersion and cyclodextrin inclusion; meanwhile, the C of AJS-SMEDDS was about 2- and 40-fold as great as the two controls, respectively. In summary, the present SMEDDS enhanced oral bioavailability of AJS and was a promising strategy to orally deliver the drug. [ABSTRACT FROM AUTHOR]

A combination therapy of metformin hydrochloride (MH) and repaglinide (RG) achieves a perfect glycemic control; however, the combination formulation of immediate release must be taken several times a day, compromising the therapeutic benefits and causing inconveniences to the patients. Herein, a bilayer matrix tablet that aimed at continuously releasing both MH and RG over time was developed, in which the two drugs were formulated into two separated layers. The tablets were prepared by wet granulation method, and the optimized formulation was obtained by evaluating the factors that affected the drug release. The bilayer tablets simultaneously released the two drugs over 12 h; and a better in vivo performance with a steady plasma concentration, markedly lower C, prolonged T, and perfect absorption was obtained. Summarily, the bilayer matrix tablets sustained both MH and RG release over time, thereby prolonging the actions for diabetic therapy and producing better health outcomes. [ABSTRACT FROM AUTHOR]

Cytoglobin, generated using genetic engineering method, is a kind of recombinant human stellate cell activation-associated protein. We speculate that it could influence the development of hepatic fibrosis like Sellate cell activation-associated protein which was discovered by Kawada et al. Therefore, we investigated its anti-fibrosis effect on liver both in vivo and in vitro. During our research, we found that cytoglobin showed obvious effect compared with the control group on Thioacetamide-induced liver fibrosis in SD rats, including significantly decrease in aspartate aminotransferase, Hyaluronic acid, laminin and collagen I(Col I) levels in serum and hydroxyproline in livers, which are the important indices reflecting the degree of hepatic fibrosis. Meanwhile, the viability of rat hepatic stellate cell line T6 (HSC-T6) cells was inhibited by cytoglobin and the apoptosis induced by cytoglobin in HSC-T6 cells was detected by Annexin V/PI double staining. Activation of the caspase cascade including caspase-3 for the intrinsic pathways was demonstrated. The results also showed that the expression of Bcl-2 protein decreased whereas that of Bax protein increased, leading to an increase of the Bax/Bcl-2 ratio. Our results demonstrated that cytoglobin exhibited anti-fibrosis activity on livers in vivo and in vitro, involving apoptosis induction. [ABSTRACT FROM AUTHOR]

Co-delivery of microRNAs and chemotherapeutic drugs into tumor cells is an attractive strategy for synergetic breast cancer therapy due to their complementary mechanisms. In this work, a core-shell nanocarrier coated by cationic albumin was developed to simultaneously deliver miRNA-34a and docetaxel (DTX) into breast cancer cells for improved therapeutic effect. The co-delivery nanocarriers showed a spherical morphology with an average particle size of 183.9 nm, and they efficiently protected miRNA-34a from degradation by RNase and serum. Importantly, the nanocarriers entered the cytosol via a caveolae-mediated pathway without entrapment in endosomes/lysosomes, thus improving the utilization of the cargo. In vitro, the co-delivery nanocarriers suppressed the expression of anti-apoptosis gene Bcl-2 at both transcription and protein levels, inhibited tumor cell migration and efficiently induced cell apoptosis and cytotoxicity. In vivo, the co-delivery nanocarriers prolonged the blood circulation of DTX, enhanced tumor accumulation of the cargo and significantly inhibited tumor growth and metastasis in 4T1-tumor bearing mice models. Taken together, the present nanocarrier co-loading with DTX and miRNA-34a is a new nanoplatform for the combination of insoluble drugs and gene/protein drugs and provides a promising strategy for the treatment of metastatic breast cancer. [ABSTRACT FROM AUTHOR]