Formulation, antileukemia mechanism, pharmacokinetics, and biodistribution of a novel liposomal emodin

Emodin is a multifunctional Chinese traditional medicine with poor water solubility. D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a pegylated vitamin E derivate. In this study, a novel liposomal-emodin-conjugating TPGS was formulated and compared with methoxypolyethyleneglycol 2000-derivatized distearoyl-phosphatidylethanolamine (mPEG2000–DSPE) liposomal emodin. TPGS improved the encapsulation efficiency and stability of emodin egg phosphatidylcholine/cholesterol liposomes. A high encapsulation efficiency of 95.2% ± 3.0%, particle size of 121.1 ± 44.9 nm, spherical ultrastructure, and sustained in vitro release of TPGS liposomal emodin were observed; these were similar to mPEG2000–DSPE liposomes. Only the zeta potential of −13.1 ± 2.7 mV was significantly different to that for mPEG2000–DSPE liposomes. Compared to mPEG2000–DSPE liposomes, TPGS liposomes improved the cytotoxicity of emodin on leukemia cells by regulating the protein levels of myeloid cell leukemia 1 (Mcl-1), B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein, which was further enhanced by transferrin. TPGS liposomes prolonged the circulation time of emodin in the blood, with the area under the concentration–time curve (AUC) 1.7 times larger than for free emodin and 0.91 times larger than for mPEG2000–DSPE liposomes. In addition, TPGS liposomes showed higher AUC for emodin in the lung and kidney than for mPEG2000–DSPE liposomes, and both liposomes elevated the amount of emodin in the heart. Overall, TPGS is a pegylated agent that could potentially be used to compose a stable liposomal emodin with enhanced therapeutics

Rapid Preparation of Spherical Granules via the Melt Centrifugal Atomization Technique

Granules with superior fluidity and low moisture absorption are ideal for tableting and capsule filling. Melt granulation as a solvent-free technology has attracted increasing interest for the granulation of moisture-sensitive drugs. The objective of the present study was to develop a solvent-less and high throughput melt granulation method via the melt centrifugal atomization (MCA) technique. The granule formability of various drugs and excipients via MCA and their dissolution properties were studied. It was found that the yield, fluidity, and moisture resistance of the granules were affected by the drug and excipient types, operation temperature, and collector diameter. The drugs were in an amorphous state in pure drug granules, or were highly dispersed in excipients as solid dispersions. The granules produced via MCA showed an improved drug dissolution. The present study demonstrated that the solvent-free, one-step, and high-throughput MCA approach can be used to produce spherical granules with superior fluidity and immediate drug release characteristics for poorly water-soluble and moisture-sensitive therapeutics

Multiple Unpinned Dirac Points in Group-Va Single-layers with Phosphorene Structure

Emergent Dirac fermion states underlie many intriguing properties of graphene, and the search for them constitute one strong motivation to explore two-dimensional (2D) allotropes of other elements. Phosphorene, the ultrathin layers of black phosphorous, has been a subject of intense investigations recently, and it was found that other group-Va elements could also form 2D layers with similar puckered lattice structure. Here, by a close examination of their electronic band structure evolution, we discover two types of Dirac fermion states emerging in the low-energy spectrum. One pair of (type-I) Dirac points is sitting on high-symmetry lines, while two pairs of (type-II) Dirac points are located at generic $k$-points, with different anisotropic dispersions determined by the reduced symmetries at their locations. Such fully-unpinned (type-II) 2D Dirac points are discovered for the first time. In the absence of spin-orbit coupling, we find that each Dirac node is protected by the sublattice symmetry from gap opening, which is in turn ensured by any one of three point group symmetries. The spin-orbit coupling generally gaps the Dirac nodes, and for the type-I case, this drives the system into a quantum spin Hall insulator phase. We suggest possible ways to realize the unpinned Dirac points in strained phosphorene.Comment: 30 pages, 6 figure

Severe Pneumonia Caused by Coinfection With Influenza Virus Followed by Methicillin-Resistant Staphylococcus aureus Induces Higher Mortality in Mice

Background: Coinfection with influenza virus and bacteria is a major cause of high mortality during flu pandemics. Understanding the mechanisms behind such coinfections is of utmost importance both for the clinical treatment of influenza and the prevention and control of epidemics.Methods: To investigate the cause of high mortality during flu pandemics, we performed coinfection experiments with H1N1 influenza virus and Staphylococcus aureus in which mice were infected with bacteria at time points ranging from 0 to 7 days after infection with influenza virus.Results: The mortality rates of mice infected with bacteria were highest 0–3 days after infection with influenza virus; lung tissues extracted from these co-infected mice showed higher infiltrating cells and thicker lung parenchyma than lung samples from coinfected mice in which influenza virus was introduced at other times and sequences. The levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-8, and IL-6 in the 0–3 day coinfected group were significantly higher than those in the other groups (p < 0.01), as were the mRNA levels of IFN-γ, IL-6, and TNF-α. Coinfection with influenza virus and S. aureus led to high mortality rates that are directly dependent on the sequence and timing of infection by both pathogens. Moreover, coinfection following this particular schedule induced severe pneumonia, leading to increased mortality.Conclusions: Our data suggest that prevention of bacterial co-infection in the early stage of influenza virus infection is critical to reducing the risk of clinical mortality

Mechanistic study on rapid fabrication of fibrous films via centrifugal melt spinning

Fibrous films have attracted considerable attention in the field of drug delivery and wound dressings owing to their porous structure and highly aligned fiber orientation. However, current fabrication methods such as electrospinning have certain limitations, including high voltage requirement and conductivity dependency. This has greatly hindered the product development and applications of fibrous films. The objective of the present study was to develop a high throughput and solventless fiber fabrication method via centrifugal melt spinning (CMS) technology. A mechanistic study on the rapid fabrication of drug-loaded fibrous films was conducted using different model drugs and polymers. It was observed that the formability, morphology, and yield of fibrous films were affected by melt rheological properties of film components, operation temperature, and plasticizers. Maintaining suitable fluidity of molten materials during the CMS process is critical for the fiber formation. The produced fibrous films had high drug loading, highly aligned orientation and modulatable drug dissolution characteristics. Finally, computational fluid dynamics (CFD) was used to simulate the melt flow fields during the CMS process. Pressure, turbulence, velocity, and partial pathlines were simulated to elucidate the influence of various operation parameters (i.e. rotating speed, inlet rate and collecting radius) and material properties (i.e. density and viscosity) on the outlet velocity of products and sample collection position. The present study demonstrated that CMS is a high throughput and cost-efficient fabrication method for drug-loaded fibrous films. CFD simulation can be used to assist in understanding fiber formation as well as optimization of CMS process parameters

Fabrication and evaluation of dental fillers using customized molds via 3D printing technology

In view of the high incidence and long-term treatment of dental caries, personalized dental fillers with long therapeutic action have broad application prospects in the dental clinic. The objective of this study was to fabricate and evaluate novel dental fillers using state-of-the-art 3D printing technology. Tinidazole (TNZ), a commonly used antibacterial drug in the dental clinic, was chosen as the model compound. Models of molars with carious cavities were obtained via 3D scanning. TNZ dental fillers were indirectly produced by thermal pressing using customized 3D printed molds. In addition, bio-relevant in vitro dissolution and mechanical testing methods were developed using customized 3D printed release and compression molds, respectively. It was observed that the formability, mechanical properties, and release behavior of the TNZ dental fillers were affected by mold materials, plasticizers, and release modifiers. The developed dental fillers were capable of sustained releasing TNZ over one week. The TNZ release characteristics can be tailored based on clinical requirements by varying hydroxypropyl methylcellulose E5 (HPMC-E5) concentrations and filler dimensions. Moreover, computational simulation based on the finite element method showed that the biomechanical behavior of the TNZ dental fillers met the daily use requirement. The present study demonstrated that the state-of-the-art 3D printing technology can be used to design and fabricate personalized dental fillers with high mechanical strength and “on-demand” drug release characteristics

Modified mixed nanomicelles with collagen peptides enhanced oral absorption of Cucurbitacin B: preparation and evaluation

Polymer nanoparticles modified with collagen peptides (CPs) are an attractive strategy for the oral delivery of active ingredients from Chinese medicine. Thus, in the present study, collagen cationic CPs were simply separated using ion-exchange resin from bovine CPs, to modify mixed nanomicelles (MMs) on the surface to improve the oral bioavailability of Cucurbitacin B (CuB). The physicochemical property of micelles was characterized, which confirmed the successful modification of the nanomicelles. CPs-modified nanomicelles in vitro were found to significantly increase cellular uptake and transportation. Compared to unmodified micelles, the quantity of CPs-modified micelles internalized by Caco-2 cells were 3.74 times greater and the cumulative transportation flux (AP-BL) was 2.81 times greater. The membrane transportation process of CuB-MMs-CPs was found to be associated with energy consumption and clathrin- and caveolin-mediated endocytosis. In vivo studies performed on rats indicated that in comparison to CuB and CuB-MMs, the relative bioavailability of CuB-MMs-CPs increased by 3.43 times and 2.14 times, respectively. In addition, the tumor inhibition caused by CuB-MMs-CPs was increased significantly. Therefore, the nanomicelles co-modified with isolated CPs could act as attractive carriers for oral delivery of CuB

Functional and Structural Characterization of a Receptor-Like Kinase Involved in Germination and Cell Expansion in Arabidopsis

Leucine-rich repeat receptor-like kinases (LRR-RLKs) are widespread in different plant species and play important roles in growth and development. Germination inhibition is vital for the completion of seed maturation and cell expansion is a fundamental cellular process driving plant growth. Here, we report genetic and structural characterizations of a functionally uncharacterized LRR-RLK, named GRACE (Germination Repression and Cell Expansion receptor-like kinase). Overexpression of GRACE in Arabidopsis exhibited delayed germination, enlarged cotyledons, rosette leaves and stubbier petioles. Conversely, these phenotypes were reversed in the T-DNA insertion knock-down mutant grace-1 plants. A crystal structure of the extracellular domain of GRACE (GRACE-LRR) determined at the resolution of 3.0 angstrom revealed that GRACE-LRR assumed a right-handed super-helical structure with an island domain (ID). Structural comparison showed that structure of the ID in GRACE-LRR is strikingly different from those observed in other LRR-RLKs. This structural observation implies that GRACE might perceive a new ligand for signaling. Collectively, our data support roles of GRACE in repressing seed germination and promoting cell expansion of Arabidopsis, presumably by perception of unknown ligand(s)

Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress

Recent studies revealed that endoplasmic reticulum (ER) stress played an emerging role of in valve calcification. Tanshinone IIA (TanIIA) has been a research hotspot in cardiovascular diseases. Previously we found that sodium TanIIA dampened the pathological phenotype transition of valvular interstitial cells (VICs) by affecting ER stress published in Chinese Journal. Here, we test the hypothesis that TanIIA attenuates the pro-osteogenic effects of oxidized low-density lipoprotein (oxLDL) in VICs by reducing induction of ER stress. Patients’ aortic valve (AV) was collected, and porcine VICs were cultured for in vitro model. ER stress markers were tested in human leaflets by immunostaining. Immunoblotting were used to test the osteoblastic factors such as Runx2, osteocalcin, and ER stress markers GRP78, CHOP, XBP1, etc. Alkakine phosphate (ALP) activity assay were used to test the activity of ALP kinase. Pro-inflammatory gene expression was detected by polymerase chain reaction. As a result, ER stress markers were elevated in patients’ calcified AVs. OxLDL induced osteogenesis and inflammation via promoting ER stress. TanIIA attenuated oxLDL induced ER stress. TanIIA also inhibited theosteoblastic factors and inflammatory cytokine expressions in VICs. In conclusion, our data provide evidence that TanIIA exerts anti-inflammation and anti-osteogenic effects in VICs by attenuating ER stress, and ER stress acts as an important regulator in oxLDL induced VICs’ phenotype transition