Towards a Graph-based Data Model for Semantics Evolution

Semantic information comes from the things being recognized and understood gradually, and thus it is often in evolution during the modeling process. Existing semantic models usually describe the objects and the relationships in an application-oriented way, which is unsuitable to reuse the schemas during the semantics evolution. In this paper, we propose a new graph-based semantic data model to overcome the limitation. SemGraph adopts a meaning-oriented approach to specifying the subjective view of the things and uses the certain meta-meaning relationships to build a graph-based semantic model. The model is simple but expressive, and is especially fit for the semantics evolution. We introduce the basic concepts and the essential mechanisms of the model, demonstrate its features with examples and typical cases of semantics evolution

Emerging nanotherapeutic strategies targeting gut-X axis against diseases

Gut microbiota can coordinate with different tissues and organs to maintain human health, which derives the concept of the gut-X axis. Conversely, the dysbiosis of gut microbiota leads to the occurrence and development of various diseases, such as neurological diseases, liver diseases, and even cancers. Therefore, the modulation of gut microbiota offers new opportunities in the field of medicines. Antibiotics, probiotics or other treatments might restore unbalanced gut microbiota, which effects do not match what people have expected. Recently, nanomedicines with the high targeting ability and reduced toxicity make them an appreciative choice for relieving disease through targeting gut-X axis. Considering this paradigm-setting trend, the current review summarizes the advancements in gut microbiota and its related nanomedicines. Specifically, this article introduces the immunological effects of gut microbiota, summarizes the gut-X axis-associated diseases, and highlights the nanotherapeutics-mediated treatment via remolding the gut-X axis. Moreover, this review also discusses the challenges in studies related to nanomedicines targeting the gut microbiota and offers the future perspective, thereby aiming at charting a course toward clinic

Effective Schema-Based XML Query Optimization Techniques

Use of path expressions is a common feature in most XML query languages, and many evaluation methods for path expression queries have been proposed recently. However, there are few researches on the issue of optimizing regular path expression queries. In this paper, two kinds of path expression optimization principles are proposed, named path shortening and path complementing, respectively. The path shortening principle reduces the querying cost by shortening the path expressions with the knowledge of XML schema. While the path complementing principle substitutes the user queries with the equivalent lower-cost path expressions. The experimental results show that these two techniques can largely improve the performance of path expression query processing

Co-amorphous solid dispersion systems of lacidipine-spironolactone with improved dissolution rate and enhanced physical stability

Co-amorphous solid dispersion (C-ASD) systems have attracted great attention to improve the solubility of poorly soluble drugs, but the selection of an appropriate stabilizer to stabilize amorphous forms is still a huge challenge. Herein, C-ASD system of two clinical combined used drugs (lacidipine (LCDP) and spironolactone (SPL)) as stabilizers to each other, was prepared by solvent evaporation method. The effects of variation in molar ratio of LCDP and SPL (3:1, 1:1, 1:3, 1:6, and 1:9) on the drug release characteristics were explored. Polarized light microscopy (PLM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were employed to evaluate the solid states. Prepared C-ASDs were further studied for their stability under the high humidity (RH 92.5%). Further analysis of C-ASDs via Fourier-transform infrared spectroscopy (FTIR) and Raman spectroscopy confirmed that hydrogen bond interactions between the two drugs played a significant role in maintaining the stability of the C-ASDs systems. Moreover, molecular dynamic (MD) simulations provided a clear insight into the stability mechanism at the molecular level. This study demonstrated the novel drug-drug C-ASDs systems is a promising formulation strategy for improved dissolution rate and enhanced physical stability of poorly soluble drugs. Keywords: Co-amorphous solid dispersion, Lacidipine, Spironolactone, Stability, Molecular dynamic (MD) simulation

Transforming a Toxic Non-Ionizable Drug into an Efficacious Liposome via Ionizable Prodrug and Remote Loading Strategies against Malignant Breast Tumors

Liposomes (lipos), one of the most successful nanotherapeutics in the clinic, have made a rapid advance over the past few years. However, still, several challenges exist for lipos for clinical practice, such as low drug loading and premature drug leakage during in vivo circulation. Paclitaxel (PTX), a commonly used first-line drug for cancer chemotherapy, was chosen as the model drug. Due to its non-ionizable and water-insoluble characteristics, the drug-loading efficiency of the marketable PTX lipos, Lipusu, is only 6.76%. Herein, we designed an ionizable PTX prodrug (PTXP) by modifying phenylboronic acid on the C2′ hydroxyl group of PTX for the remote loading of liposomal formulations through the pH gradient method. Compared with Lipusu, PTXP lipos displayed a 34% higher loading efficiency and an encapsulation efficiency of approximately 95%. A series of in vitro/vivo experiments indicated that PTXP lipos possess colloidal stability, prolonged blood circulation, high tumor site accumulation, potent anti-tumor effects, and safety. A combination of ionizable prodrugs and remote loading has proved to be an effective and simple strategy to achieve high liposomal encapsulation efficiency of poorly soluble non-ionizable drugs for clinical application

Self-assembled short peptides: Recent advances and strategies for potential pharmaceutical applications

Self-assembled short peptides have intrigued scientists due to the convenience of synthesis, good biocompatibility, low toxicity, inherent biodegradability and fast response to change in the physiological environment. Therefore, it is necessary to present a comprehensive summary of the recent advances in the last decade regarding the construction, route of administration and application of self-assembled short peptides based on the knowledge on their unique and specific ability of self-assembly. Herein, we firstly explored the molecular mechanisms of self-assembly of short peptides, such as non-modified amino acids, as well as Fmoc-modified, N-functionalized, and C-functionalized peptides. Next, cell penetration, fusion, and peptide targeting in peptide-based drug delivery were characterized. Then, the common administration routes and the potential pharmaceutical applications (drug delivery, antibacterial activity, stabilizers, imaging agents, and applications in bioengineering) of peptide drugs were respectively summarized. Last but not least, some general conclusions and future perspectives in the relevant fields were briefly listed. Although with certain challenges, great opportunities are offered by self-assembled short peptides to the fascinating area of drug development

Self-delivering prodrug-nanoassemblies fabricated by disulfide bond bridged oleate prodrug of docetaxel for breast cancer therapy

<p>Breast cancer leads to high mortality of women in the world. Docetaxel (DTX) has been widely applied as one of the first-line chemotherapeutic drugs for breast cancer therapy. However, the clinical outcome of DTX is far from satisfaction due to its poor drug delivery efficiency. Herein, a novel disulfide bond bridged oleate prodrug of DTX was designed and synthesized to construct self-delivering prodrug-based nanosystem for improved anticancer efficacy of DTX. The uniquely engineered prodrug-nanoassemblies showed redox-responsive drug release, increased cellular uptake and comparable cytotoxicity against 4T1 breast cancer cells when compared with free DTX. <i>In vivo</i>, oleate prodrug-based nanoparticles (NPs) demonstrated significantly prolonged systemic circulation and increased accumulation in tumor site. As a result, prodrug NPs produced a notable antitumor activity in 4T1 breast cancer xenograft in BALB/c mice. This prodrug-based self-assembly and self-delivery strategy could be utilized to improve the delivery efficiency of DTX for breast cancer treatment.</p

Transdermal Cubic Phases of Metformin Hydrochloride: In Silico and in Vitro Studies of Delivery Mechanisms

Transdermal delivery is one of important controlled drug release strategies for drug development. Cubic phases are the assemblies of amphiphilic molecules in water with the hydrophilic–hydrophobic interpenetrating network for transdermal delivery of both hydrophilic and hydrophobic drugs. However, many details about the transdermal delivery of drugs from cubic phases remain unclear. Here, metformin hydrochloride (Met) cubic phases were prepared with glyceryl monooleate (GMO), ethanol, and water. The cubic structure was identified with the polarizing light microscopy and small-angle X-ray scattering method. Dissipative particle dynamics (DPD) was used for building the microstructures of the cubic phases to explore the mechanism of drug release that mainly depended on drug diffusion from the water channels of cubic phases in accordance with the Higuchi equation of in vitro release experiments. The coarse-grained model and molecular docking method showed that GMO could enhance drug permeation through the skin by disturbing the interaction between Met and the skin proteins, and increasing the fluidity of skin lipids, which was confirmed with the Fourier transform infrared spectroscopy, Langmuir monolayer, and immunohistochemistry. Furthermore, in vitro permeation experiments showed the high Met transdermal improvement of cubic phases. Cubic phases are an ideal transdermal delivery system of Met. In silico methods are very useful for analyzing the molecular mechanisms of transdermal formulations

Redox-Sensitive Citronellol–Cabazitaxel Conjugate: Maintained in Vitro Cytotoxicity and Self-Assembled as Multifunctional Nanomedicine

Citronellol-cabazitaxel (CIT-ss-CTX) conjugate self-assembled nanoparticles (CSNPs) were designed and prepared by conjugating cabazitaxel with citronellol via the disulfide bond that is redox-sensitive to the high concentration of glutathione within tumor cells. Notably, the CSNPs maintained in the cell cytotoxicity. Moreover, the AUC_0‑<i>t</i> of CSNPs was 6.5-fold higher than that of cabazitaxel solutions and the <i>t</i>_1/2 was prolonged 2.3 times. Furthermore, we found that CSNPs could be employed as an efficient carrier for other hydrophobic drugs or imaging agents. Thus, the in vivo targeting study was implemented via using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR)-loaded CSNPs as imaging agent, which showed CSNPs could effectively accumulate at the tumor site. Curcumin, a hydrophobic anticancer drug, was successfully loaded in CSNPs which exhibits good stability and synergistic antitumor effects. The citronellol–cabazitaxel conjugate therefore has a promising perspective as a multifunctional nanomedicine for combination therapy and theranostics attributed to its long-circulation property, redox-sensitive mechanism, and high drug coloading capability