Synergistic treatment of osteosarcoma with biomimetic nanoparticles transporting doxorubicin and siRNA

IntroductionOsteosarcoma tumors are the most common malignant bone tumors in children and adolescents. Their treatment usually requires surgical removal of all detectable cancerous tissue and multidrug chemotherapy; however, the prognosis for patients with unresectable or recurrent osteosarcoma is unfavorable. To make chemotherapy safer and more effective for osteosarcoma patients, biomimetic nanoparticles (NPs) camouflaged by mesenchymal stem cell membranes (MSCMs) were synthesized to induce osteosarcoma cell apoptosis by co-delivering the anticancer drug doxorubicin hydrochloride(DOX) and a small interfering RNA (siRNA). Importantly, these NPs have high biocompatibility and tumor-homing ability. This study aimed to improve the efficacy of osteosarcoma therapy by using the synergistic combination of DOX and an siRNA targeting the apoptosis suppressor gene survivin.MethodsBiomimetic NPs (DOX/siSUR-PLGA@MSCM NPs) were synthesized by coloading DOX and survivin siRNA (siSUR) into poly (lactide-co-glycolide acid) (PLGA) via a double-emulsion solvent evaporation method. The NPs were camouflaged by MSCMs to deliver both DOX and survivin-targeting siRNA and characterized and evaluated in terms of cellular uptake, in vitro release, in vitro and in vivo antitumor effects, and biosafety.ResultsDOX/siSUR-PLGA@MSCM NPs had good tumor-homing ability due to the MSCMs modification. The drug-laden biomimetic NPs had good antitumor effects in homozygous MG63 tumor-bearing mice due to the synergistic effect of the drug combination.ConclusionDOX/siSUR-PLGA@MSCM NPs can show improved therapeutic effects in osteosarcoma patients due to the combination of a chemotherapeutic drug and gene therapy based on their good tumor targeting and biosafety

Structure-based inference of molecular functions of proteins of unknown function from Berkeley Structural Genomics Center

Advances in sequence genomics have resulted in an accumulation of a huge number of protein sequences derived from genome sequences. However, the functions of a large portion of them cannot be inferred based on the current methods of sequence homology detection to proteins of known functions. Three-dimensional structure can have an important impact in providing inference of molecular function (physical and chemical function) of a protein of unknown function. Structural genomics centers worldwide have been determining many 3-D structures of the proteins of unknown functions, and possible molecular functions of them have been inferred based on their structures. Combined with bioinformatics and enzymatic assay tools, the successful acceleration of the process of protein structure determination through high throughput pipelines enables the rapid functional annotation of a large fraction of hypothetical proteins. We present a brief summary of the process we used at the Berkeley Structural Genomics Center to infer molecular functions of proteins of unknown function

Fold prediction of helical proteins using torsion angle dynamics and predicted restraints

We describe a procedure for predicting the tertiary folds of α-helical proteins from their primary sequences. The central component of the procedure is a method for predicting interhelical contacts that is based on a helix-packing model. Instead of predicting the individual contacts, our method attempts to identify the entire patch of contacts that involve residues regularly spaced in the sequences. We use this component to glue together two powerful existing methods: a secondary structure prediction program, whose output serves as the input to the contact prediction algorithm, and the tortion angle dynamics program, which uses the predicted tertiary contacts and secondary structural states to assemble three-dimensional structures. In the final step, the procedure uses the initial set of simulated structures to refine the predicted contacts for a new round of structure calculation. When tested against 24 small to medium-sized proteins representing a wide range of helical folds, the completely automated procedure is able to generate native-like models within a limited number of trials consistently

Electrocaloric effect in ferroelectric materials: From phase field to first-principles based effective Hamiltonian modeling

Electrocaloric effect (ECE) of ferroelectrics has attracted considerable interest due to its potential application in environmentally friendly solid-state refrigeration. The discovery of giant ECE in ferroelectric thin films has greatly renewed the research activities and significantly stimulated experimental and theoretical investigations. In this review, the recent progress on the theoretical modeling of ECE in ferroelectric and antiferroelectric materials are introduced, which mainly focuses on the phase field modeling and first-principles based effective Hamiltonian method. We firstly provide the theoretical foundation and technique details for each method. Then a comprehensive review on the progress in the application of two methods and the strategies to tune the ECE are presented. Finally, we outline the practical procedure on the development of multi-scale computational method without experiemtal parameters for the screening of optimized electrocaloric materials

Anisotropic Icephobic Mechanisms of Textured Surface: Barrier or Accelerator?

Icing has been seen as an economic and safety hazard due to its threats to aviation, power generation, offshore platforms, etc., where passive icephobic surfaces with a surface texturing design have the potential to address this problem. However, the intrinsic icephobic principles associated with the surface textures, energy, elasticity, and hybrid effects are still unclear. To explore the anisotropic wettability, ice nucleation, and ice detaching behaviors, a series of textured poly(dimethylsiloxane) (PDMS)-based coatings with various texture orientations were proposed through a simple stamping method with surface functionalization. The anisotropic hydrophobic/icephobic phenomena and mechanisms were discovered from wettability evaluation, experimentally studied by icing/deicing experiments, and finally verified by microscopic numerical simulations. One-way analysis of variance (one-way ANOVA analysis) was used to analyze the effect of surface textures on hydrophobic/icephobic properties, which assisted in understanding anisotropic phenomena. Typical anisotropic ice nucleation and growth on the textured coatings were clarified using in situ environmental scanning electron microscope (ESEM) characterization. The ice/coating interfacial stress responses were studied by numerical stimulation at the microscopic level, further verifying the localized, amplified, and propagated stress at the ice/coating interface. The theoretical anisotropic responses, barrier effect, and accelerating effect were verified to interpret the anisotropic wettability and icephobicity, depending on the specific surface conditions. This study revealed the basics of the anisotropic icephobic mechanisms of textured icephobic surfaces, further facilitating the R&D of passive icephobic surfaces

Depletion of gut microbiota resistance in 5×FAD mice enhances the therapeutic effect of mesenchymal stem cell-derived exosomes

Mesenchymal stem cell-derived exosomes (MSCs-exo) can be used for treating Alzheimer’s disease (AD) by promoting amyloid-β (Aβ) degradation, modulating immune responses, protecting neurology, promoting axonal growth, and improving cognitive impairment. Increasing evidence suggests that the alteration of gut microbiota is closely related to the occurrence and development of Alzheimer's disease. In this study, we hypothesized that dysbiosis of gut microbiota might limit the therapy of MSCs-exo, and the application of antibiotics would improve the therapy. Methods: In this original research study, we used MSCs-exo to treat 5 ×FAD mice and fed them antibiotic cocktails for 1 week to detect cognitive ability and neuropathy. The mice’s feces were collected to investigate alterations in the microbiota and metabolites. Results: The results revealed that the AD gut microbiota eliminated the therapeutic effect of MSCs-exo, whereas antibiotic modulation of disordered gut microbiota and associated metabolites enhanced the therapeutic effect of MSCs-exo. Conclusions: These results encourage the research of novel therapeutics to enhance MSCs-exo treatment for AD, which could benefit a broader range of patients with AD

Engineering of Bacillus thuringiensis Cry Proteins to Enhance the Activity against Western Corn Rootworm

A novel Bacillus thuringiensis Cry protein, Cry8Hb, active against Diabrotica virgifera virgifera (Western corn rootworm, WCRW) was discovered. Unexpectedly, the anti-rootworm activity of the Cry8Hb toxin was enhanced significantly by fusing Escherichia coli maltose binding protein (MBP) to this Cry toxin. While the exact mechanism of the activity enhancement remains indefinite, it is probable that the enhancement is a result of increased solubility of the MBP-Cry8Hb fusion in the rootworm midgut. This hypothesis was examined using a synthetic Cry3 protein called IP3-1, which was not soluble at a neutral pH like Cry8Hb and marginally active to WCRW. When IP3-1 was fused to MBP, its anti-WCRW activity was enhanced 13-fold. To further test the hypothesis, DNA shuffling was performed on IP3-1 to increase the solubility without MBP. Screening of shuffled libraries found six new IP3 variants showing very high anti-WCRW activity without MBP. Sequence and 3D structure analysis of those highly active, shuffled IP3 variants revealed several charge-altering mutations such as Lys to Glu on the putative MBP-attaching side of the IP3 molecule. It is likely that those mutations make the protein acidic to substitute the functions of MBP including enhancing the solubility of IP3 at a neutral pH