l-Peptide functionalized dual-responsive nanoparticles for controlled paclitaxel release and enhanced apoptosis in breast cancer cells

Nanoparticles and macromolecular carriers have been widely used to increase the efficacy of chemotherapeutics, largely through passive accumulation provided by their enhanced permeability and retention effect. However, the therapeutic efficacy of nanoscale anticancer drug delivery systems is severely truncated by their low tumor-targetability and inefficient drug release at the target site. Here, the design and development of novel l-peptide functionalized dual-responsive nanoparticles (l-CS-g-PNIPAM-PTX) for active targeting and effective treatment of GRP78-overexpressing human breast cancer in vitro and in vivo are reported. l-CS-g-PNIPAM-PTX NPs have a relative high drug loading (13.5%) and excellent encapsulation efficiency (74.3%) and an average diameter of 275 nm. The release of PTX is slow at pH 7.4 and 25 °C but greatly accelerated at pH 5.0 and 37 °C. MTT assays and confocal experiments showed that the l-CS-g-PNIPAM-PTX NPs possessed high targetability and antitumor activity toward GRP78 overexpressing MDA-MB-231 human breast cancer cells. As expected, l-CS-g-PNIPAM-PTX NPs could effectively treat mice bearing MDA-MB-231 human breast tumor xenografts with little side effects, resulting in complete inhibition of tumor growth and a high survival rate over an experimental period of 60 days. These results indicate that l-peptide-functionalized acid - and thermally activated - PTX prodrug NPs have a great potential for targeted chemotherapy in breast cancer.</p

Functionalized MoS2 nanosheet-capped periodic mesoporous organosilicas as a multifunctional platform for synergistic targeted chemo-photothermal therapy

The combination of different therapies into a single platform has attracted increasing attention as a potential synergistic tumor treatment. Herein, the fabrication of a novel folate targeted system for chemo-photothermal therapy by using thioether-bridged periodic mesoporous organosilica nanoparticles (PMOs) as a drug-loading vehicle is described. The novel targeted molecular bovine serum albumin-folic acid-modified MoS2 sheets (MoS2-PEI-BSA-FA) were successfully synthesized and characterized, and then utilized as a capping agent to block PMOs to control the drug release and to investigate their potential in near-infrared photothermal therapy. The resulting PMOs–DOX@MoS2–PEI-BSA-FA complexes had a uniform diameter (196 nm); high DOX loading capacity (185 mg/g PMOs-SH); excellent photothermal transformation ability; and good biocompatibility in physiological conditions. The PMOs–DOX@MoS2–PEI-BSA-FA exhibited pH-dependence and near infrared (NIR) laser irradiation-triggered DOX release. In vitro experimental results confirmed that the material exhibits excellent photothermal transfer ability, outstanding tumor killing efficiency and specificity to target tumor cells via an FA-receptor-mediated endocytosis process. The in vivo experiments further demonstrated that the platform for synergistic chemo-photothermal therapy could significantly inhibit tumor growth, which is superior to any monotherapy. Meanwhile, cytotoxicity assays and histological assessments show that the engineered PMOs@MoS2–PEI-BSA-FA have good biocompatibility, further inspiring potential biomedical applications. Overall, this work describes an excellent drug delivery system for chemo-photothermal synergistic targeted therapy having good drug release properties, which have great potential in cancer therapy

Crosstalk between Platelets and the Immune System: Old Systems with New Discoveries

Platelets are small anucleate cells circulating in the blood. It has been recognized for more than 100 years that platelet adhesion and aggregation at the site of vascular injury are critical events in hemostasis and thrombosis; however, recent studies demonstrated that, in addition to these classic roles, platelets also have important functions in inflammation and the immune response. Platelets contain many proinflammatory molecules and cytokines (e.g., P-selectin, CD40L, IL-1β, etc.), which support leukocyte trafficking, modulate immunoglobulin class switch, and germinal center formation. Platelets express several functional Toll-like receptors (TLRs), such as TLR-2, TLR-4, and TLR-9, which may potentially link innate immunity with thrombosis. Interestingly, platelets also contain multiple anti-inflammatory molecules and cytokines (e.g., transforming growth factor-β and thrombospondin-1). Emerging evidence also suggests that platelets are involved in lymphatic vessel development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2. Besides the active contributions of platelets to the immune system, platelets are passively targeted in several immune-mediated diseases, such as autoimmune thrombocytopenia, infection-associated thrombocytopenia, and fetal and neonatal alloimmune thrombocytopenia. These data suggest that platelets are important immune cells and may contribute to innate and adaptive immunity under both physiological and pathological conditions

Comprehensive ab initio study of effects of alloying elements on generalized stacking fault energies of Ni and Ni3_3Al

Excellent high-temperature mechanical properties of Ni-based single crystal superalloys (NSCSs) are attributed to the yield strength anomaly of Ni$_{3}$Al that is intimately related to generalized stacking fault energies (GSFEs). Therefore, clarifying the effects of alloying elements on the GSFEs is of great significance for alloys design. Here, by means of ab initio density functional theory calculations, we systematically calculated the GSFEs of different slip systems of Ni and Ni$_{3}$Al without and with alloying elements using the alias shear method. We obtained that for Ni, except for magnetic elements Mn, Fe, and Co, most of alloying elements decrease the unstable stacking fault energy ($\gamma_{usf}$) of the $[01\bar{1}](111)$ and $[11\bar{2}](111)$ slip systems and also decrease the stable stacking fault energy ($\gamma_{sf}$) of the $[11\bar{2}](111)$ slip system. For Ni$_{3}$Al, most of alloying elements in groups IIIB-VIIB show a strong Al site preference. Except for Mn and Fe, the elements in groups VB-VIIB and the first column of group VIII increase the values of $\gamma_{usf}$ of different slip systems of Ni$_{3}$Al. On the other hand, the elements in groups IIIB-VIIB also increase the value of $\gamma_{sf}$. We found that Re is an excellent strengthening alloying element that significantly increases the slip barrier of the tailing slip process for Ni, and also enhances the slip barrier of the leading slip process of three slip systems for Ni$_{3}$Al. W and Mo exhibit similar effects as Re. We predicted that Os, Ru, and Ir are good strengthening alloying elements as well, since they show the strengthening effects on both the leading and tailing slip process for Ni and Ni$_{3}$Al

Proteomic analysis of spinal cord tissue in a rat model of cancer-induced bone pain

BackgroundCancer-induced bone pain (CIBP) is a moderate to severe pain and seriously affects patients’ quality of life. Spinal cord plays critical roles in pain generation and maintenance. Identifying differentially expressed proteins (DEPs) in spinal cord is essential to elucidate the mechanisms of cancer pain.MethodsCIBP rat model was established by the intratibial inoculation of MRMT-1 cells. Positron emission tomography (PET) scan and transmission electron microscopy (TEM) were used to measure the stats of spinal cord in rats. Label free Liquid Chromatography with tandem mass spectrometry (LC-MS-MS) were used to analyze the whole proteins from the lumbar spinal cord. Differentially expressed proteins (DEPs) were performed using Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, and verified using Western blot and immunofluorescence assay.ResultsIn the current study, CIBP rats exhibited bone damage, spontaneous pain, mechanical hyperalgesia, and impaired motor ability. In spinal cord, an hypermetabolism and functional abnormality were revealed on CIBP rats. An increase of synaptic vesicles density in active zone and a disruption of mitochondrial structure in spinal cord of CIBP rats were observed. Meanwhile, 422 DEPs, consisting of 167 up-regulated and 255 down-regulated proteins, were identified among total 1539 proteins. GO enrichment analysis indicated that the DEPs were mainly involved in catabolic process, synaptic function, and enzymic activity. KEGG pathway enrichment analysis indicated a series of pathways, including nervous system disease, hormonal signaling pathways and amino acid metabolism, were involved. Expression change of synaptic and mitochondrial related protein, such as complexin 1 (CPLX1), synaptosomal-associated protein 25 (SNAP25), synaptotagmin 1 (SYT1), aldehyde dehydrogenase isoform 1B1 (ALDH1B1), Glycine amidinotransferase (GATM) and NADH:ubiquinone oxidoreductase subunit A11 (NDUFA11), were further validated using immunofluorescence and Western blot analysis.ConclusionThis study provides valuable information for understanding the mechanisms of CIBP, and supplies potential therapeutic targets for cancer pain

Insights into the vertical stratification of microbial ecological roles across the deepest seawater column on Earth

The Earth’s oceans are a huge body of water with physicochemical properties and microbial community profiles that change with depth, which in turn influences their biogeochemical cycling potential. The differences between microbial communities and their functional potential in surface to hadopelagic water samples are only beginning to be explored. Here, we used metagenomics to investigate the microbial communities and their potential to drive biogeochemical cycling in seven different water layers down the vertical profile of the Challenger Deep (0–10,500 m) in the Mariana Trench, the deepest natural point in the Earth’s oceans. We recovered 726 metagenome-assembled genomes (MAGs) affiliated to 27 phyla. Overall, biodiversity increased in line with increased depth. In addition, the genome size of MAGs at ≥4000 m layers was slightly larger compared to those at 0–2000 m. As expected, surface waters were the main source of primary production, predominantly from Cyanobacteria. Intriguingly, microbes conducting an unusual form of nitrogen metabolism were identified in the deepest waters (>10,000 m), as demonstrated by an enrichment of genes encoding proteins involved in dissimilatory nitrate to ammonia conversion (DNRA), nitrogen fixation and urea transport. These likely facilitate the survival of ammonia-oxidizing archaea α lineage, which are typically present in environments with a high ammonia concentration. In addition, the microbial potential for oxidative phosphorylation and the glyoxylate shunt was enhanced in >10,000 m waters. This study provides novel insights into how microbial communities and their genetic potential for biogeochemical cycling differs through the Challenger deep water column, and into the unique adaptive lifestyle of microbes in the Earth’s deepest seawater

DiTing: A pipeline to infer and compare biogeochemical pathways from metagenomic and metatranscriptomic data

Metagenomics and metatranscriptomics are powerful methods to uncover key micro-organisms and processes driving biogeochemical cycling in natural ecosystems. Databases dedicated to depicting biogeochemical pathways (for example, metabolism of dimethylsulfoniopropionate (DMSP), which is an abundant organosulfur compound) from metagenomic/metatranscriptomic data are rarely seen. Additionally, a recognized normalization model to estimate the relative abundance and environmental importance of pathways from metagenomic and metatranscriptomic data has not been organized to date. These limitations impact the ability to accurately relate key microbial-driven biogeochemical processes to differences in environmental conditions. Thus, an easy-to-use, specialized tool that infers and visually compares the potential for biogeochemical processes, including DMSP cycling, is urgently required. To solve these issues, we developed DiTing, a tool wrapper to infer and compare biogeochemical pathways among a set of given metagenomic or metatranscriptomic reads in one step, based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) and a manually created DMSP cycling gene database. Accurate and specific formulae for over 100 pathways were developed to calculate their relative abundance. Output reports detail the relative abundance of biogeochemical pathways in both text and graphical format. DiTing was applied to simulated metagenomic data and resulted in consistent genetic features of simulated benchmark genomic data. Subsequently, when applied to natural metagenomic and metatranscriptomic data from hydrothermal vents and the Tara Ocean project, the functional profiles predicted by DiTing were correlated with environmental condition changes. DiTing can now be confidently applied to wider metagenomic and metatranscriptomic datasets, and it is available at https://github.com/xuechunxu/DiTing

Core-sheath nanofibers as drug delivery system for thermoresponsive controlled release

In this work, a smart drug delivery system of core–sheath nanofiber is reported. The core-sheath nanofibers were prepared with thermoresponsive poly-(N-isopropylacrylamide) (PNIPAAm) (as core) and hydrophobic ethylcellulose (EC) (as sheath) by coaxial electrospinning. Analogous medicated fibers were prepared by loading with a model drug ketoprofen (KET). The fibers were cylindrical without phase separation and have visible core-sheath structure as shown by scanning and transmission electron microscopy. X-ray diffraction patterns demonstrated the drug with the amorphous physical form was present in the fiber matrix. Fourier transform infrared spectroscopy analysis was conducted, finding that there were significant intermolecular interactions between KET and the polymers. Water contact angle measurements proved that the core-sheath fibers from hydrophobic transformed into hydrophobic when the temperature reached the lower critical solution temperature. In vitro drug-release study of nanofibers with KET displayed that the coaxial nanofibers were able to synergistically combine the characteristics of the two polymers producing a temperature-sensitive drug delivery system with sustained release properties. In addition, they were established to be non-toxic and suitable for cell growth. These findings show that the core–sheath nanofiber is a potential candidate for controlling drug delivery system

Plant Food Delphinidin-3-Glucoside Significantly Inhibits Platelet Activation and Thrombosis: Novel Protective Roles against Cardiovascular Diseases

Delphinidin-3-glucoside (Dp-3-g) is one of the predominant bioactive compounds of anthocyanins in many plant foods. Although several anthocyanin compounds have been reported to be protective against cardiovascular diseases (CVDs), the direct effect of anthocyanins on platelets, the key players in atherothrombosis, has not been studied. The roles of Dp-3-g in platelet function are completely unknown. The present study investigated the effects of Dp-3-g on platelet activation and several thrombosis models in vitro and in vivo. We found that Dp-3-g significantly inhibited human and murine platelet aggregation in both platelet-rich plasma and purified platelets. It also markedly reduced thrombus growth in human and murine blood in perfusion chambers at both low and high shear rates. Using intravital microscopy, we observed that Dp-3-g decreased platelet deposition, destabilized thrombi, and prolonged the time required for vessel occlusion. Dp-3-g also significantly inhibited thrombus growth in a carotid artery thrombosis model. To elucidate the mechanisms, we examined platelet activation markers via flow cytometry and found that Dp-3-g significantly inhibited the expression of P-selectin, CD63, CD40L, which reflect platelet α- and δ-granule release, and cytosol protein secretion, respectively. We further demonstrated that Dp-3-g downregulated the expression of active integrin αIIbβ3 on platelets, and attenuated fibrinogen binding to platelets following agonist treatment, without interfering with the direct interaction between fibrinogen and integrin αIIbβ3. We found that Dp-3-g reduced phosphorylation of adenosine monophosphate-activated protein kinase, which may contribute to the observed inhibitory effects on platelet activation. Thus, Dp-3-g significantly inhibits platelet activation and attenuates thrombus growth at both arterial and venous shear stresses, which likely contributes to its protective roles against thrombosis and CVDs