Gestodene, a novel positive allosteric modulator of PAR1, enhances PAR1-mediated human platelet aggregation.

Background: Protease-activated receptor 1 (PAR1) is expressed in human platelets and can be activated by low concentrations of thrombin. Vorapaxar, a selective antagonist of PAR1, inhibits thrombin-induced calcium mobilization in human platelet, which is associated with an increased risk of bleeding. Conversely, the administration of a positive allosteric modulator (PAM) of PAR1 may pose a substantial risk of thrombosis due to inducing excessive platelet activation. In this study, we discovered a novel PAM of PAR1 and investigated the effect of enhanced PAR1 activation by PAM of PAR1 on platelet activation. Methods: To find PAMs of PAR1, a cell-based screen was performed in HT29 cells, and finally, gestodene, an oral contraceptive drug (OC), was identified as a novel PAM of PAR1. The mechanism of action of gestodene and its effects on platelet activation were investigated in human megakaryocytic leukemia cell line MEG-01 cells and human platelet. Results: Gestodene enhanced both thrombin- and PAR1-activating peptide (AP)-induced intracellular calcium levels in a dose-dependent manner without altering PAR2 and PAR4 activity. Gestodene significantly increased PAR1-AP-induced internalization of PAR1 and phosphorylation of ERK1/2, and the enhancing effects were significantly blocked by vorapaxar. Furthermore, gestodene potently increased PAR1-AP induced morphological changes in MEG-01 cells. Remarkably, in human blood, gestodene exerted a robust augmentation of PAR1-AP-induced platelet aggregation, and vorapaxar effectively attenuated the gestodene-induced enhancement of platelet aggregation mediated by PAR1. Conclusion: Gestodene is a selective PAM of PAR1 and suggest one possible mechanism for the increased risk of venous thromboembolism associated with OCs containing gestodene.

Discovery of Protease-activated receptor 2 antagonists derived from phenylalanine for the treatment of breast cancer.

Protease-activated receptor 2 (PAR2) has garnered attention as a potential therapeutic target in breast cancer. PAR2 is implicated in the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) via G protein and beta-arrestin pathways, contributing to the proliferation and metastasis of breast cancer cells. Despite the recognized role of PAR2 in breast cancer progression, clinically effective PAR2 antagonists remain elusive. To address this unmet clinical need, we synthesized and evaluated a series of novel compounds that target the orthosteric site of PAR2. Using in silico docking simulations, we identified compound 9a, an optimized derivative of compound 1a ((S)-N-(1-(benzylamino)-1-oxo-3-phenylpropan-2-yl)benzamide), which exhibited enhanced PAR2 antagonistic activity. Subsequent molecular dynamics simulations comparing 9a with the partial agonist 9d revealed that variations in ligand-induced conformational changes and interactions dictated whether the compound acted as an antagonist or agonist of PAR2. The results of this study suggest that further development of 9a could contribute to the advancement of PAR2 antagonists as potential therapeutic agents for breast cancer.

Anticancer Effect of Hemin through ANO1 Inhibition in Human Prostate Cancer Cells.

Anoctamin1 (ANO1), a calcium-activated chloride channel, is overexpressed in a variety of cancer cells, including prostate cancer, and is involved in cancer cell proliferation, migration, and invasion. Inhibition of ANO1 in these cancer cells exhibits anticancer effects. In this study, we conducted a screening to identify novel ANO1 inhibitors with anticancer effects using PC-3 human prostate carcinoma cells. Screening of 2978 approved and investigational drugs revealed that hemin is a novel ANO1 inhibitor with an IC50 value of 0.45 µM. Notably, hemin had no significant effect on intracellular calcium signaling and cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP (cAMP)-regulated chloride channel, and it showed a weak inhibitory effect on ANO2 at 3 µM, a concentration that completely inhibits ANO1. Interestingly, hemin also significantly decreased ANO1 protein levels and strongly inhibited the cell proliferation and migration of PC-3 cells in an ANO1-dependent manner. Furthermore, it strongly induced caspase-3 activation, PARP degradation, and apoptosis in PC-3 cells. These findings suggest that hemin possesses anticancer properties via ANO1 inhibition and could be considered for development as a novel treatment for prostate cancer.

Interface engineered cascade-type electronic structure of 2D/0D/2D CdS-CdCO3/SnO2 quantum dots/g-C3N4 nanocomposite for boosting solar-driven photocatalysis.

A rational design of heterojunctions with high-quality contacts is essential for efficiently separating photogenerated charge carries and boosting the solar-driven harvesting capability. Herein, we fabricated a novel heterojunction of SnO2 quantum dots-anchored CdS-CdCO3 with g-C3N4 nanosheets as a superior photocatalyst. SnO2 quantum dots (SQDs) with positively charged surfaces were tightly anchored on the negatively charged surface of CdS nanosheets (NSs). The resulting CdS@SnO2 was finally decorated with g-C3N4 NSs, and a new crystalline phase of CdS-CdCO3 was formed during the hydrothermal decoration process, g-C3N4 decorated CdS-CdCO3@SnO2 (CdS-CdCO3@SnO2@g-C3N4). The as-synthesized photocatalysts were evaluated for the degradation of methyl orange dye under solar light conditions. The CdS-CdCO3@SnO2@g-C3N4 exhibited 7.7-fold and 2.3-fold enhancements in photocatalytic activities in comparison to those of the bare CdS and CdS@SnO2 NSs, respectively. The optimal performance of CdS-CdCO3@SnO2@g-C3N4 is primarily attributed to the cascade-type conduction band alignments between 2D/0D/2D heterojunctions, which can harvest maximum solar light and effectively separate photoexcited charge carriers. This work provides a new inspiration for the rational design of 2D/0D/2D heterojunction photocatalyst for green energy generation and environmental remediation applications.

Design Optimization of a Soft Robotic Rehabilitation Glove Based on Finger Workspace Analysis.

The finger workspace is crucial for performing various grasping tasks. Thus, various soft rehabilitation gloves have been developed to assist individuals with paralyzed hands in activities of daily living (ADLs) or rehabilitation training. However, most soft robotic glove designs are insufficient to assist with various hand postures because most of them use an underactuated mechanism for design simplicity. Therefore, this paper presents a methodology for optimizing the design of a high-degree-of-freedom soft robotic glove while not increasing the design complexity. We defined the required functional workspace of the index finger based on ten frequently used grasping postures in ADLs. The design optimization was achieved by simulating the proposed finger-robot model to obtain a comparable workspace to the functional workspace. In particular, the moment arm length for extension was optimized to facilitate the grasping of large objects (precision disk and power sphere), whereas a torque-amplifying routing design was implemented to aid the grasping of small objects (lateral pinch and thumb-two-finger pinch). The effectiveness of the optimized design was validated through testing with a stroke survivor and comparing the assistive workspace. The observed workspace demonstrated that the optimized glove design could assist with nine out of the ten targeted grasping posture functional workspaces. Furthermore, the assessment of the grasping speed and force highlighted the glove's usability for various rehabilitation activities. We also present and discuss a generalized methodology to optimize the design parameters of a soft robotic glove that uses an underactuated mechanism to assist the targeted workspace. Overall, the proposed design optimization methodology serves as a tool for developing advanced hand rehabilitation robots, as it offers insight regarding the importance of routing optimization in terms of the workspace.

Anticancer Evaluation of Novel Benzofuran-Indole Hybrids as Epidermal Growth Factor Receptor Inhibitors against Non-Small-Cell Lung Cancer Cells.

The epidermal growth factor receptor (EGFR), also known as ErbB1 and HER1, belongs to the receptor tyrosine kinase family. EGFR serves as the primary driver in non-small-cell lung cancer (NSCLC) and is a promising therapeutic target for NSCLC. In this study, we synthesized a novel chemical library based on a benzofuran-indole hybrid scaffold and identified 8aa as a potent and selective EGFR inhibitor. Interestingly, 8aa not only showed selective anticancer effects against NSCLC cell lines, PC9, and A549, but it also showed significant inhibitory effects against the double mutant L858R/T790M EGFR, which frequently occurs in NSCLC. In addition, in PC9 and A549 cells, 8aa potently blocked the EGFR signaling pathway, cell viability, and cell migration. These findings suggest that 8aa, a benzofuran-indole hybrid derivative, is a novel EGFR inhibitor that may be a potential candidate for the treatment of NSCLC patients with EGFR mutations.

Functional MRI Assessment of Brain Activity During Hand Rehabilitation with an MR-Compatible Soft Glove in Chronic Stroke Patients: A Preliminary Study.

Brain plasticity plays a significant role in functional recovery after stroke, but the specific benefits of hand rehabilitation robot therapy remain unclear. Evaluating the specific effects of hand rehabilitation robot therapy is crucial in understanding how it impacts brain activity and its relationship to rehabilitation outcomes. This study aimed to investigate the brain activity pattern during hand rehabilitation exercise using functional magnetic resonance imaging (fMRI), and to compare it before and after 3-week hand rehabilitation robot training. To evaluate it, an fMRI experimental environment was constructed to facilitate the same hand posture used in rehabilitation robot therapy. Two stroke survivors participated and the conjunction analysis results from fMRI scans showed that patient 1 exhibited a significant improvement in activation profile after hand rehabilitation robot training, indicative of improved motor function in the bilateral motor cortex. However, activation profile of patient 2 exhibited a slight decrease, potentially due to habituation to the rehabilitation task. Clinical results supported these findings, with patient 1 experiencing a greater increase in FMA score than patient 2. These results suggest that hand rehabilitation robot therapy can induce different brain activity patterns in stroke survivors, which may be linked to patient-specific training outcomes. Further studies with larger sample sizes are necessary to confirm these findings.

Inhibition of ANO1 by Cis- and Trans-Resveratrol and Their Anticancer Activity in Human Prostate Cancer PC-3 Cells.

Anoctamin1 (ANO1), a calcium-activated chloride channel, is involved in the proliferation, migration, and invasion of various cancer cells including head and neck squamous cell carcinoma, lung cancer, and prostate cancer. Inhibition of ANO1 activity or downregulation of ANO1 expression in these cancer cells is known to exhibit anticancer effects. Resveratrol, a natural polyphenol abundant in wines, grapes, berries, soybeans, and peanuts, shows a wide variety of biological effects including anti-inflammatory, antioxidant, and anticancer activities. In this study, we investigated the effects of two stereoisomers of resveratrol on ANO1 activity and found that cis- and trans-resveratrol inhibited ANO1 activity with different potencies. Cis- and trans-resveratrol inhibited ANO1 channel activity with IC50 values of 10.6 and 102 µM, respectively, and had no significant effect on intracellular calcium signaling at 10 and 100 µM, respectively. In addition, cis-resveratrol downregulated mRNA and protein expression levels of ANO1 more potently than trans-resveratrol in PC-3 prostate cancer cells. Cis- and trans-resveratrol significantly reduced cell proliferation and cell migration in an ANO1-dependent manner, and both resveratrol isomers strongly increased caspase-3 activity, PARP cleavage, and apoptotic sub-G1 phase ratio in PC-3 cells. These results revealed that cis-resveratrol is a potent inhibitor of ANO1 and exhibits ANO1-dependent anticancer activity against human metastatic prostate cancer PC-3 cells.

Cooperative Hand Therapy via a Soft, Wearable, and Unilateral Telerobotic System.

Functional rehabilitation of the hand is a complex and difficult process involving a large number of degrees of freedom (DOFs). Soft wearable hand-rehabilitation robots have assisted hand movements with a compact structural design, but effective rehabilitation requires an intuitive control scheme that can manage many DOFs and incorporate interaction with an occupational therapist, which has yet to be developed for this type of device. Thus, we present a soft wearable unilateral telerobotic system that enables various grasping tasks and cooperative interaction between the patient and therapist. The presented system consists of a sensor glove that measures the hand postures of the occupational therapist and a soft robotic glove that assists 4-DOF movements of the patient's hand, including adjustments of the interjoint coordination of the finger and 2-DOF movements of the thumb (flexion/extension and opposition/reposition). The soft robotic glove effectuates hand movements based on the measurements from the sensor glove. A telerobotic impedance-control scheme provides intuitive guidance of various hand postures, along with a fingertip-force vector. The feasible workspace and control performance of the system were evaluated on a healthy recruit and a poststroke patient. The presented system allowed the therapist to increase the patient's thumb workspace by 400% in palmar-dorsal direction and to control the fingertip-force direction at -30°âˆ¼10° range by enabling control of interjoint coordination of the proximal-interphalangeal and metacarpophalangeal joints. These features facilitate patients to perform various postures for stable object grasping. The presented rehabilitation system is suitable for noncontact telehealthcare that facilitates patient-therapist interactions.

Synthesis and Biological Evaluation of a Fused Structure of Indolizine and Pyrrolo[1,2-c]pyrimidine: Identification of Its Potent Anticancer Activity against Liver Cancer Cells.

A highly efficient approach to a new indolizine scaffold fused with pyrrolo[1,2-c]pyrimidine was achieved via one-pot three-component coupling followed by an oxidative cyclization reaction. The simple two-step sequence allowed rapid access to various tetracyclic compounds from commercially available starting materials with the formation of five new bonds. Here, we observed the effects of these compounds on cell viability in HepG2, H1299, HT29, AGS, and A549 cancer cell lines. Interestingly, this fused scaffold had more potent anticancer activity in hepatocellular carcinoma HepG2 and Huh7 cells than other cancer cells. In particular, 5r strongly decreased cell viability in HepG2 and Huh7 cells with an IC50 value of 0.22 ± 0.08 and 0.10 ± 0.11 µM, respectively, but had a very weak inhibitory effect on the cell viability of other cancer cell lines. In addition, 5r significantly inhibited cell migration and induced apoptosis in HepG2 and Huh7 cells via the activation of caspase-3 and cleavage of PARP in a dose-dependent manner. Notably, the co-treatment of 5r with gemcitabine resulted in the significant additional inhibition of cell viability in HepG2 and Huh7 cells. Our results suggest that 5r could be used to develop new chemotype anticancer agents against liver cancers.

Berbamine Reduces Chloroquine-Induced Itch in Mice through Inhibition of MrgprX1.

Chloroquine (CQ) is an antimalaria drug that has been widely used for decades. However, CQ-induced pruritus remains one of the major obstacles in CQ treatment for uncomplicated malaria. Recent studies have revealed that MrgprX1 plays an essential role in CQ-induced itch. To date, a few MrgprX1 antagonists have been discovered, but they are clinically unavailable or lack selectivity. Here, a cell-based high-throughput screening was performed to identify novel antagonists of MrgprX1, and the screening of 2543 compounds revealed two novel MrgprX1 inhibitors, berbamine and closantel. Notably, berbamine potently inhibited CQ-mediated MrgprX1 activation (IC50 = 1.6 µM) but did not alter the activity of other pruritogenic GPCRs. In addition, berbamine suppressed the CQ-mediated phosphorylation of ERK1/2. Interestingly, CQ-induced pruritus was significantly reduced by berbamine in a dose-dependent manner, but berbamine had no effect on histamine-induced, protease-activated receptors 2-activating peptide-induced, and deoxycholic acid-induced itch in mice. These results suggest that berbamine is a novel, potent, and selective antagonist of MrgprX1 and may be a potential drug candidate for the development of therapeutic agents to treat CQ-induced pruritus.

Motivation for MOOC learning persistence: An expectancy-value theory perspective.

Managing learning continuity is critical for successful MOOC learning. Thus, enabling learners to have learning persistence needs to be integrated into the MOOC learning design. Motivation effort is a critical component enabling students to maintain continuous MOOC learning. The expectancy-value theory explains why learners engage in learning: (1) they have a higher perceived ability for learning success, (2) place value on learning, and (3) avoid psychological costs. However, it is unclear how these factors affect MOOC learning persistence and how learners' motivation is formed from this perspective. This experimental study explored how learners' motivational variables affect their learning persistence, focusing on the expectancy-value theory. The results of this study indicated that academic self-efficacy and task value had significant positive effects on learning persistence. The structural relationship of antecedent, process, and outcome variables showed that teaching presence as an antecedent had a significantly positive effect on academic self-efficacy and task value. Among the three factors of the expectancy-value theory, only the task value influenced learning persistence through student engagement as a mediator. Based on the results, suggestions are provided for motivating MOOC environments that support learners' continuous MOOC learning.

EEG-EMG hybrid real-time classification of hand grasp and release movements intention in chronic stroke patients.

Rehabilitation of the hand motor function is essential for stroke patients to resume activities of daily living. Recent studies have shown that wearable robot systems, like a multi degree-of-freedom soft glove, have the potential to improve hand motor impairment. The rehabilitation system, which is intuitively controlled according to the user's intention, is expected to induce active participation of the user and further promote brain plasticity. However, due to the patient-specific nature of stroke patients, extracting the intention from stroke patients is still challenging. In this study, we implemented a classifier that combines EEG and EMG to detect chronic stroke patients' four types of intention: rest, grasp, hold, and release. Three chronic stroke patients participated in the experiment and performed rest, grasp, hold, and release actions. The rest vs. grasp binary classifier and release vs. hold binary classifier showed 76.9% and 86.6% classification accuracy in real-time, respectively. In addition, patient-specific accuracy comparisons showed that the hybrid approach was robust to upper limb impairment level compared to other approaches. We believe that these results could pave the way for the development of BCI-based robotic hand rehabilitation therapy.

GB83, an Agonist of PAR2 with a Unique Mechanism of Action Distinct from Trypsin and PAR2-AP.

Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor (GPCR) activated by proteolytic cleavage of its N-terminal domain. Once activated, PAR2 is rapidly desensitized and internalized by phosphorylation and ß-arrestin recruitment. Due to its irreversible activation mechanism, some agonists that rapidly desensitized PAR2 have been misconceived as antagonists, and this has impeded a better understanding of the pathophysiological role of PAR2. In the present study, we found that GB83, initially identified as a PAR2 antagonist, is a bona fide agonist of PAR2 that induces unique cellular signaling, distinct from trypsin and PAR2-activating peptide (AP). Activation of PAR2 by GB83 markedly elicited an increase in intracellular calcium levels and phosphorylation of MAPKs, but in a delayed and sustained manner compared to the rapid and transient signals induced by trypsin and PAR2-AP. Interestingly, unlike PAR2-AP, GB83 and trypsin induced sustained receptor endocytosis and PAR2 colocalization with ß-arrestin. Moreover, the recovery of the localization and function of PAR2 was significantly delayed after stimulation by GB83, which may be the reason why GB83 is recognized as an antagonist of PAR2. Our results revealed that GB83 is a bona fide agonist of PAR2 that uniquely modulates PAR2-mediated cellular signaling and is a useful pharmacological tool for studying the pathophysiological role of PAR2.

Anticancer effect of verteporfin on non-small cell lung cancer via downregulation of ANO1.

Anoctamin 1 (ANO1) is a calcium-activated chloride channel found in various cell types and is overexpressed in non-small cell lung cancer (NSCLC), a major cause of cancer-related mortality. With the rising interest in development of druggable compounds for NSCLC, there has been a corresponding rise in interest in ANO1, a novel drug target for NSCLC. However, as ANO1 inhibitors that have been discovered simultaneously exhibit both the functions of an inhibition of ANO1 channel as well as a reduction of ANO1 protein levels, it is unclear which of the two functions directly causes the anticancer effect. In this study, verteporfin, a chemical compound that reduces ANO1 protein levels was identified through high-throughput screening. Verteporfin did not inhibit ANO1-induced chloride secretion but reduced ANO1 protein levels in a dose-dependent manner with an IC50 value of ~300 nM. Moreover, verteporfin inhibited neither P2Y receptor-induced intracellular Ca2+ mobilization nor cystic fibrosis transmembrane conductance regulator (CFTR) channel activity, and molecular docking studies revealed that verteporfin bound to specific sites of ANO1 protein. Confirming that verteporfin reduces ANO1 protein levels, we then investigated the molecular mechanisms involved in its effect on NSCLC cells. Interestingly, verteporfin decreased ANO1 protein levels, the EGFR-STAT3 pathway as well as ANO1 mRNA expression. Verteporfin reduced the viability of ANO1-expressing cells (PC9, and gefitinib-resistant PC9) and induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage. However, it did not affect hERG channel activity. These results show that the anticancer mechanism of verteporfin is caused via the down-regulation of ANO1.

Generation of a poly-functionalized indolizine scaffold and its anticancer activity in pancreatic cancer cells.

A highly efficient domino [4 + 2] annulation process was employed to construct a novel indolizine chemical scaffold. Biological investigation led us to identify 6w as a potent anticancer agent. 6w significantly inhibited cell viability in BxPC3 pancreatic cancer, MCF7 breast cancer, and PC3 prostate cancer cell lines with IC50 values of 0.47 ± 0.04, 1.82 ± 0.08 and 2.68 ± 0.08 µM, respectively. Remarkably, 6w showed a weak effect on cell viability of nontumorigenic human keratinocyte cell line HaCaT compared to the above three types of cancer cells. 6w most potently inhibited cell viability of BxPC3 cells, and 6w also potently reduced cell migration and induced apoptosis in BxPC3 cells through activation of caspase-3 and cleavage of PARP in a dose-dependent manner. These results suggest that 6w can be used for the development of potential anticancer drugs for the treatment of pancreatic cancer.

Development and Clinical Evaluation of a Novel Foot Stretching Robot That Simultaneously Stretches Plantar Fascia and Achilles Tendon for Treatment of Plantar Fasciitis.

OBJECTIVE: This paper presents the development and clinical evaluation of a foot stretching robot that simultaneously stretches the plantar fascia and Achilles tendon for the treatment of plantar fasciitis. The therapeutic effectiveness of the robot and feasibility of using metatarsophalangeal joint stiffness as an indicator of recovery were identified through the clinical evaluations. METHODS: The robot implements an effective foot stretching protocol through a novel mechanism design that simultaneously stretches the plantar fascia and Achilles tendon using a single motor. Thirty patients with plantar fasciitis and fifteen healthy participants volunteered in the cross-sectional clinical evaluation, and nine patients from the patients group participated in the one-month clinical trial. Four main outcomes (Foot Function Index, Visual Analogue Scale-Foot and Ankle, plantar fascia thickness, and metatarsophalangeal joint stiffness) were used for the clinical evaluations. RESULTS: In the cross-sectional clinical evaluation, the symptomatic feet of patients showed moderate negative correlation between normalized metatarsophalangeal joint stiffness and plantar fascia thickness with statistical significance. In the one-month clinical trial, all the main outcomes showed significant improvement after using the developed robot. Comparing our results with previous studies also indicated a therapeutic superiority of our robot for treating plantar fasciitis. CONCLUSION: Our foot stretching robot had significant therapeutic effect on plantar fasciitis, and normalized metatarsophalangeal joint stiffness measured by our robot could be used as a monitoring indicator for recovery from plantar fasciitis. SIGNIFICANCE: This study contributed to practical issues related to treatment of plantar fasciitis, and our results could be applied to effective treatment of plantar fasciitis and progressive monitoring of recovery.

A zero-dimensional/two-dimensional Ag-Ag2S-CdS plasmonic nanohybrid for rapid photodegradation of organic pollutant by solar light.

Herein, the two synthesis strategies are employed for rational design of 0D/2DAg-Ag2S-CdS heterojunctions towards photocatalytic degradation of methyl orange (MO) under simulated solar light. As the first strategy, a ternary Ag-Ag2S-CdS nanosheet (NS) heterojunction was fabricated via combined cation exchange and photo-reduction (CEPR) method (Ag-Ag2S-CdS/CEPR). The second strategy employed coprecipitation (CP) method (Ag-Ag2S-CdS/CP). Strikingly, SEM, TEM and HR-TEM images are manifested the first strategy is beneficial for retaining the original thickness (20.2 nm) of CdS NSs with a dominant formation of metallic Ag, whereas the second strategy increases the thickness (33.4 nm) of CdS NSs with a dominant formation of Ag2S. The Ag-Ag2S-CdS/CEPR exhibited 1.8-fold and 3.5-fold enhancement in photocatalytic activities as compared to those of Ag-Ag2S-CdS/CP and bare CdS NSs, respectively. This enhanced photocatalytic activity could be ascribed to fact that the first strategy produces a high-quality interface with intimate contact between the Ag-Ag2S-CdS heterojunctions, resulting in enhanced separation of photo-excited charge carriers, extended light absorption, and enriched active-sites. Furthermore, the degradation efficiency of Ag-Ag2S-CdS/CEPR was significantly reduced to ∼5% in the presence of BQ (•O2- scavenger), indicating that •O2- is the major active species that can decompose MO dye under simulated solar light.

Bioinspired High-Degrees of Freedom Soft Robotic Glove for Restoring Versatile and Comfortable Manipulation.

The human hand is one of the most complex and compact grippers that has arisen as a product of natural genetic engineering; it is highly versatile, as it handles power and precision tasks. Since proper contact points and force directions are required to ensure versatility and secure a stable grip on an object, there must be a large workspace and controllable tip force directions for the digits. Although they are important, many individuals with neuromuscular diseases experience loss of these features. Thus, we propose a high-degree-of-freedom (DOF) soft robotic glove inspired by the anatomical features of human hands. The mechanism for adjusting the position and force direction of each tip is based on the structure of the extrinsic and intrinsic muscle-tendon units. The large thumb workspace was achieved by assisting opposition/reposition and flexion/extension to enable various grasping postures. A bidirectional actuation control mechanism with a cable-actuated agonist and an elastomer antagonist increased the assisted DOF and maintained compactness. The kinematic and kinetic performances of our device were evaluated by performing tests with eight stroke survivors. The thumb workspace increased by 43%, 207%, and 248% in the distal-proximal, dorsal-palmar, and radial-ulnar directions, respectively. The pinching shear force decreased by 54% and 45% for the nonthumb digits and thumb, respectively. These device-assisted improvements allowed objects to be stably grasped and manipulated in various postures. The novel device can assist individuals with impaired hand function to improve their grasping performance. Clinical Research Information Service (CRIS) Registration Number: KCT0004855.

Cinobufagin Exerts Anticancer Activity in Oral Squamous Cell Carcinoma Cells through Downregulation of ANO1.

Anoctamin1 (ANO1), a calcium-activated chloride channel, is frequently overexpressed in several cancers, including oral squamous cell carcinoma (OSCC). OSCC is a highly aggressive cancer and the most common oral malignancy. ANO1 has been proposed as a potential candidate for targeted anticancer therapy. In this study, we performed a cell-based screening to identify novel regulators leading to the downregulation of ANO1, and discovered cinobufagin, which downregulated ANO1 expression in oral squamous cell carcinoma CAL-27 cells. ANO1 protein levels were significantly reduced by cinobufagin in a dose-dependent manner with an IC50 value of ~26 nM. Unlike previous ANO1 inhibitors, short-term (≤10 min) exposure to cinobufagin did not alter ANO1 chloride channel activity and ANO1-dependent intestinal smooth muscle contraction, whereas long-term (24 h) exposure to cinobufagin significantly reduced phosphorylation of STAT3 and mRNA expression of ANO1 in CAL-27 cells. Notably, cinobufagin inhibited cell proliferation of CAL-27 cells expressing high levels of ANO1 more potently than that of ANO1 knockout CAL-27 cells. In addition, cinobufagin significantly reduced cell migration and induced caspase-3 activation and PARP cleavage in CAL-27 cells. These results suggest that downregulation of ANO1 by cinobufagin is a potential mechanism for the anticancer effect of cinobufagin in OSCC.