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RNF146 is an E3 ubiquitin ligase that specifically recognizes and polyubiquitinates poly (ADP-ribose) (PAR)-conjugated substrates for proteasomal degradation. RNF146 has been shown to be neuroprotective against PAR polymerase-1 (PARP1)-induced cell death during stroke. Here we report that RNF146 expression and RNF146 inducers can prevent cell death elicited by Parkinson’s disease (PD)-associated and PARP1-activating stimuli. In SH-SY5Y cells, RNF146 expression conferred resistance to toxic stimuli that lead to PARP1 activation. High-throughput screen using a luciferase construct harboring the RNF146 promoter identified liquiritigenin as an RNF146 inducer. We found that RNF146 expression by liquiritigenin was mediated by estrogen receptor activation and contributed to cytoprotective effect of liquiritigenin. Finally, RNF146 expression by liquiritigenin in mouse brains provided dopaminergic neuroprotection in a 6-hydroxydopamine PD mouse model. Given the presence of PARP1 activity and RNF146 deficits in PD, it could be a potential therapeutic strategy to restore RNF146 expression by natural compounds or estrogen receptor activation.

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. The coumarin glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC50 values of 7.22 and 14.77 µM, respectively, and also moderately inhibited MAO-B (29.48 µM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC50 = 36.68 µM). Liquiritigenin (LG) potently inhibited MAO-B (IC50 = 0.098 µM) and MAO-A (IC50 = 0.27 µM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (>40 µM). GC was a reversible, noncompetitive inhibitor of BChE with a Ki value of 4.47 µM, and LG was a reversible competitive inhibitor of MAO-B with a Ki value of 0.024 µM. Docking simulations showed that the binding affinity of GC for BChE (−7.8 kcal/mol) was greater than its affinity for AChE (−7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 Å, respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (−8.8 kcal/mol) was greater than its affinity for MAO-A (−7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer’s disease with multi-targeting activities.

Paeonia suffruticosa has been extensively used as a traditional medicine with various beneficial effects; paeonolide (PALI) was isolated from its dried roots. This study aimed to investigate the novel effects and mechanisms of PALI in pre-osteoblasts. Here, cell viability was evaluated using an MTT assay. Early and late osteoblast differentiation was examined by analyzing the activity of alkaline phosphatase (ALP) and by staining it with Alizarin red S (ARS). Cell migration was assessed using wound healing and Boyden chamber assays. Western blot and immunofluorescence analyses were used to examine the intracellular signaling pathways and differentiation proteins. PALI (0.1, 1, 10, 30, and 100 μM) showed no cytotoxic or proliferative effects in pre-osteoblasts. In the absence of cytotoxicity, PALI (1, 10, and 30 μM) promoted wound healing and transmigration during osteoblast differentiation. ALP staining demonstrated that PALI (1, 10, and 30 μM) promoted early osteoblast differentiation in a dose-dependent manner, and ARS staining showed an enhanced mineralized nodule formation, a key indicator of late osteoblast differentiation. Additionally, low concentrations of PALI (1 and 10 μM) increased the bone morphogenetic protein (BMP)–Smad1/5/8 and Wnt–β-catenin pathways in osteoblast differentiation. Particularly, PALI (1 and 10 μM) increased the phosphorylation of ERK1/2 compared with BMP2 treatment, an FDA-approved drug for bone diseases. Furthermore, PALI-mediated early and late osteoblast differentiation was abolished in the presence of the ERK1/2 inhibitor U0126. PALI-induced RUNX2 (Cbfa1) expression and nuclear localization were also attenuated by blocking the ERK1/2 pathway during osteoblast differentiation. We suggest that PALI has biologically novel activities, such as enhanced osteoblast differentiation and bone mineralization mainly through the intracellular ERK1/2-RUNX2 signaling pathway, suggesting that PALI might have therapeutic action and aid the treatment and prevention of bone diseases, such as osteoporosis and periodontitis.

Sanguisorba officinalis L. (Rosaceae) is a perennial herbaceous plant and its roots have been used as an important traditional medicine for over 2000 years. Ziyuglycoside I (Ziyu), an active compound isolated from the roots of S. officinalis L., has shown biological effects such as anti-oxidant, antiviral, and antiwrinkle activities. This study aimed to elucidate the underlying mechanisms of action of Ziyu on cytotoxicity, migration, and differentiation of pre-osteoblasts. Herein, at concentrations ranging from 1 to 100 [Formula: see text]M, Ziyu was not cytotoxic against pre-osteoblasts. Alkaline phosphatase activity assay and staining, and migration assay showed that Ziyu increased cell migration and promoted early osteoblast differentiation, followed by the enhancement of mineralized nodule formation in a dose-dependent manner, as indicated by Alizarin Red S staining. In addition, Ziyu increased the protein levels of runt-related transcription factor 2 (RUNX2) during osteoblast differentiation, whereas it did not affect the phosphorylation of Smad1/5/8 and GSK3b and expression of [Formula: see text]-catenin. Ziyu also activated ERK1/2 and mitogen-activated protein kinase during osteoblast differentiation, and ERK1/2 inhibitor attenuated Ziyu-mediated RUNX2 expression and nuclear accumulation. Furthermore, Ziyu-mediated early and late osteoblast differentiation was significantly suppressed by the inhibition of ERK1/2, which was accompanied by attenuation in the mRNA levels of osteoblast-related genes including bone sialoprotein, osteopontin, and osteocalcin. Taken together, the findings of this study provide evidence that Ziyu promotes cell migration, osteoblast differentiation, and bone mineralization and suggest a potential role for Ziyu in the treatment of bone diseases.

Vast applications and services have been enabled as the number of mobile or sensing devices with communication capabilities has grown. However, managing the devices, integrating networks or combining services across different networks has become a new problem since each network is not directly connected via back-end core networks or servers. The issue is and has been discussed especially in wireless sensor and actuator networks (WSAN). In such systems, sensors and actuators are tightly coupled, so when an independent WSAN needs to collaborate with other networks, it is difficult to adequately combine them into an integrated infrastructure. In this paper, we propose drone-as-a-gateway (DaaG), which uses drones as mobile gateways to interconnect isolated networks or combine independent services. Our system contains features that focus on the service being provided in the order of importance, different from an adaptive simple mobile sink system or delay-tolerant system. Our simulation results have shown that the proposed system is able to activate actuators in the order of importance of the service, which uses separate sensors’ data, and it consumes almost the same time in comparison with other path-planning algorithms. Moreover, we have implemented DaaG and presented results in a field test to show that it can enable large-scale on-demand deployment of sensing and actuation infrastructure or the Internet of Things (IoT).

Background: Plant extracts have long been regarded as useful medicines in the treatment of human diseases. Rubia cordifolia Nakai has been used as a traditional medicine, as it has pharmacological properties such as antioxidant and anti-inflammatory activity. However, the biological functions of TMARg, isolated from the roots of R. cordifolia, in osteoblast differentiation remain unknown. This study was performed to investigate the pharmacological effects and intracellular signaling of TMARg in the osteoblast differentiation of pre-osteoblast MC3T3-E1 cells and mesenchymal precursor C2C12 cells. Methods: Cell viability was evaluated using an MTT assay. Early and late osteoblast differentiation was examined by analyzing the activity of alkaline phosphatase (ALP), and by staining it with Alizarin red S (ARS). Cell migration was determined by using migration assays. Western blot analysis and immunocytochemical analysis were used to examine the intracellular signaling pathways and differentiation proteins. Results: In the present study, TMARg showed no cytotoxicity and increased the osteoblast differentiation in pre-osteoblasts, as assessed from the alkaline phosphate (ALP) staining and activity and ARS staining. TMARg also induced BMP2 expression and increased the p-smad1/5/8-RUNX2 and β-catenin pathways in both MC3T3-E1 and C2C12 cells. Furthermore, TMARg activated mitogen-activated protein kinases (MAPKs) and increased the cell migration rate. In addition, the TMARg-mediated osteoblast differentiation was suppressed by BMP and Wnt inhibitors with the downregulation of BMP2 expression. Conclusion: These findings demonstrate that TMARg exerts pharmacological and biological effects on osteoblast differentiation through the activation of BMP2 and β-catenin signaling pathways, and suggest that TMARg might be a potential phytomedicine for the treatment of bone diseases.