Inhibition of RANKL-Induced Osteoclastogenesis by Novel Mutant RANKL

Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments.     

Targeted Delivery of Anesthetic Agents to Bone Tissues using Conductive Microneedles Enhanced Iontophoresis for Painless Dental Anesthesia

Pain management during dental procedures is a cornerstone for successful daily practice. In current practice, the traditional needle and syringe injection is used to administer local anesthesia. However, the appearance of long needles and the pain associated with it often leads to dental anxiety deterring timely interventions. Microneedles (MNs) have emerged as a minimally invasive alternative to hypodermic needles and shown to be effective in transdermal drug delivery applications. In this article, the potential use of MNs for local anesthesia delivery in dentistry is explored. The development of a novel conductive MN array that can be used in combination with iontophoresis technique to achieve drug penetration through the oral mucosa and the underlying bone tissue is presented. The conductive MN array plays a dual-role, creating micro-conduits and lowering the resistance of the oral mucosa. The reduced tissue resistance further enhances the application of a low-voltage current that is able to direct and accelerate the drug molecules to target the sensory nerves supplying teeth. The successful delivery of lidocaine using this new strategy in a clinically relevant rabbit incisor model is shown to be as effective as the current gold standard.     

Magnetically Guidable Proteinaceous Adhesive Microbots for Targeted Locoregional Therapeutics Delivery in the Highly Dynamic Environment of the Esophagus

The esophagus is a tubular-shaped muscular organ where swallowed fluids and muscular contractions constitute a highly dynamic environment. The turbulent, coordinated processes that occur through the oropharyngeal conduit can often compromise targeted administration of therapeutic drugs to a lesion, significantly reducing therapeutic efficacy. Here, magnetically guidable drug vehicles capable of strongly adhering to target sites using a bioengineered mussel adhesive protein (MAP) to achieve localized delivery of therapeutic drugs against the hydrodynamic physiological conditions are proposed. A suite of highly uniform microparticles embedded with iron oxide (IO) nanoparticles (MAP@IO MPs) is microfluidically fabricated using the genipin-mediated covalent cross-linking of bioengineered MAP. The MAP@IO MPs are successfully targeted to a specific region and prolongedly retained in the tubular-structured passageway. In particular, orally administered MAP@IO MPs are effectively captured in the esophagus in vivo in a magnetically guidable manner. Moreover, doxorubicin (DOX)-loaded MAP@IO MPs exhibit a sustainable DOX release profile, effective anticancer therapeutic activity, and excellent biocompatibility. Thus, the magnetically guidable locomotion and robust underwater adhesive properties of the proteinaceous soft microbots can provide an intelligent modular approach for targeted locoregional therapeutics delivery to a specific lesion site in dynamic fluid-associated tubular organs such as the esophagus.     

A Lane-Level Road Marking Map Using a Monocular Camera

The essential requirement for precise localization of a self-driving car is a lane-level map which includes road markings (RMs). Obviously, we can build the lane-level map by running a mobile mapping system (MMS) which is equipped with a high-end 3D LiDAR and a number of high-cost sensors. This approach, however, is highly expensive and ineffective since a single high-end MMS must visit every place for mapping. In this paper, a lane-level RM mapping system using a monocular camera is developed. The developed system can be considered as an alternative to expensive high-end MMS. The developed RM map includes the information of road lanes (RLs) and symbolic road markings (SRMs). First, to build a lane-level RM map, the RMs are segmented at pixel level through the deep learning network. The network is named RMNet. The segmented RMs are then gathered to build a lane-level RM map. Second, the lane-level map is improved through loop-closure detection and graph optimization. To train the RMNet and build a lane-level RM map, a new dataset named SeRM set is developed. The set is a large dataset for lane-level RM mapping and it includes a total of 25157 pixel-wise annotated images and 21000 position labeled images. Finally, the proposed lane-level map building method is applied to SeRM set and its validity is demonstrated through experimentation.      

Synthesis and luminescence properties of reddish-orange-emitting Ca2GdNbO6:Sm3+ phosphors with good thermal stability for high CRI white applications

Novel reddish-orange-emitting Ca₂GdNbO₆:Sm³⁺ phosphors based on the emission of ⁴G_5/2 → ⁶H_9/2 transition at 651 nm with the chromatic coordinate of (0.633, 0.366) were synthesized. The crystal structure and chemical purity were identified in detail. Under the 407 nm excitation, the optimum concentration of Sm³⁺ ion was found to be 5 mol% dominated by the dipole-dipole interaction in the Ca₂GdNbO₆ host material. The color purity of the sample with optimum doping was estimated to be about 78.38%. Besides, the thermal stability was also studied, and it was further found that the emission intensity remained 65.32% at 423 K. The packaged white LED device exhibited excellent CRI and CCT values of 92.43 and 4896 K. Finally, the polydimethylsiloxane film with a stable structure and flexible property was prepared. These above results reveal that novel reddish-orange-emitting Ca₂GdNbO₆:Sm³⁺ phosphors can be applied in high CRI white communication and flexible display applications.     

Phenotypic Discovery of SB1501, an Anti-obesity Agent,through Modulating Mitochondrial Activity

Obesity has become a pandemic that threatens the quality of life and discovering novel therapeutic agents that can reverse obesity and obesity-related metabolic disorders are necessary. Here, we aimed to identify new anti-obesity agents using a phenotype-based approach. We performed image-based high-content screening with a fluorogenic bioprobe (SF44), which visualizes cellular lipid droplets (LDs), to identify initial hit compounds. A structure-activity relationship study led us to yield a bioactive compound SB1501, which reduces cellular LDs in 3T3-L1 adipocytes without cytotoxicity. SB1501 induced the expression of gene products that regulate mitochondrial biogenesis and fatty acid oxidation in 3T3-L1 adipocytes. Daily treatment with SB1501 improved the metabolic states of db/db mice by reducing body fat mass, adipose tissue mass, food intake, and increasing glucose tolerance. The anti-obesity effect of SB1501 may result from perturbation of the PGC-1α–UCP1 regulatory axis in inguinal white adipose tissue and brown adipose tissue. These data suggest the therapeutic potential of SB1501 as an anti-obesity agent via modulating mitochondrial activities.     

Combination of vegetable soup and glucan demonstrates synergistic effects on macrophage-mediated immune responses

Vegetable soup (VS), a plant-based functional food, has been used as a traditional folk medicine and is attracting attention for its ability to enhance the immune response. β-Glucan, a well-established and effective immunomodulator, has synergistic effects when used in combination with some bioactive compounds. In the present study, we aimed to evaluate the synergistic immunomodulatory effects of the combination of VS and β-glucan on macrophage-mediated immune responses. β-Glucan was demonstrated to synergistically enhance the VS-stimulated immune response, including the production of interleukin-6, tumor necrosis factor-α, and nitric oxide, mainly through the mitogen-activated protein kinase pathway in macrophages. In addition, this combination has the potential for further development in functional foods with immune-enhancing activity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10068-021-00888-x.     

Aqueous dispersion of 1D van der Waals Mo6S3I6 crystal using biocompatible tri-block copolymer

To achieve the stable dispersion of 1D van der Waals crystal Mo₆S₃I₆ in aqueous media, the tri-block copolymer (Poloxamer) is used as dispersant. The head group of Poloxamer, hydrophobic polypropylene oxide parts can be adsorbed to Mo₆S₃I₆ surface by hydrophobic interaction and the tail group with hydrophilic polyethylene oxide exposed to the outside of the Mo₆S₃I₆ is soluble in water and can form sufficient steric hindrance, resulting in stable aqueous dispersion in nm scale. The excellent biocompatibility of aqueous dispersed nm scale 1D Mo₆S₃I₆ was demonstrated by effective proliferation of C2C12 cells.