Shape Memory Alloy (SMA) Actuators: The Role of Material, Form, and Scaling Effects.

Shape memory alloys (SMAs) are smart materials that are widely used to create intelligent devices because of their high energy density, actuation strain, and biocompatibility characteristics. Given their unique properties, SMAs are found to have significant potential for implementation in many emerging applications in mobile robots, robotic hands, wearable devices, aerospace/automotive components, and biomedical devices. Here, the state-of-the-art of thermal and magnetic SMA actuators in terms of their constituent materials, form, and scaling effects are summarized, including their surface treatments and functionalities. The motion performance of various SMA architectures (wires, springs, smart soft composites, and knitted/woven actuators) is also analyzed. Based on the assessment, current challenges of SMAs that need to be addressed for their practical application are emphasized. Finally, how to advance SMAs by synergistically considering the effects of material, form, and scale is suggested.

Novel Small-Molecule Inhibitor of NLRP3 Inflammasome Reverses Cognitive Impairment in an Alzheimer's Disease Model.

Aberrant activation of the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays an essential role in multiple diseases, including Alzheimer's disease (AD) and psoriasis. We report a novel small-molecule inhibitor, NLRP3-inhibitory compound 7 (NIC7), and its derivative, which inhibit NLRP3-mediated activation of caspase 1 along with the secretion of interleukin (IL)-1ß, IL-18, and lactate dehydrogenase. We examined the therapeutic potential of NIC7 in a disease model of AD by analyzing its effect on cognitive impairment as well as the expression of dopamine receptors and neuronal markers. NIC7 significantly reversed the associated disease symptoms in the mice model. On the other hand, NIC7 did not reverse the disease symptoms in the imiquimod (IMQ)-induced disease model of psoriasis. This indicates that IMQ-based psoriasis is independent of NLRP3. Overall, NIC7 and its derivative have therapeutic prospects to treat AD or NLRP3-mediated diseases.

Shape memory alloy-driven undulatory locomotion of a soft biomimetic ray robot.

The objective of this study was to imitate undulatory motion, which is a commonly observed swimming mechanism of rays, using a soft morphing actuator. To achieve the undulatory motion, an artificial muscle built with shape memory alloy-based soft actuators was exploited to control the shape-changing behavior of a soft fin membrane. Artificial undulating fins were divided into two categories according to the method of generating the wave motion: single and multiple actuator-driven fins. For empirical research on the transformation and propulsion behavior of each fin type, the design and construction of bound propulsors were undertaken to mimic the structural and behavioral aspects of animals. To visualize the effect of undulatory motion on the swimming efficiency test of the fin beat frequency, a simplified soft undulating fin with a rectangular propulsor was constructed and tested. Additionally, dynamic modeling of the fin tip in wave-traveling was conducted for comparison and optimization. To optimize the thrust and propulsion efficiency of robot speed, the effects of the wave amplitude control and actuator sequence on the fin behavior were examined. An untethered robot was constructed according to the experimental results of the propulsors. Both exhibited exceptional swimming efficiency and maneuverability. The multiple actuator-driven ray robot exhibited a maximum swimming speed of 0.25 body lengths per second which is almost a similar swimming speed with previously reported robots. The developed robot achieved directional swimming (forward and backward) and turning (including rotation). Underwater exploration in an artificial environment was performed using the robot.

Ginsenoside Rc Is a New Selective UGT1A9 Inhibitor in Human Liver Microsomes and Recombinant Human UGT Isoforms.

Ginseng is known to have inhibitory effects on UGT1A9 activity. However, little is known about the inhibitory effects of ginsenosides, the major active compounds in ginseng, on UGT1A9 activity. In vitro investigation of UGT1A9 inhibition by ginsenosides was carried out using human liver microsomes (HLMs). Among 10 ginsenosides, ginsenoside Rc was the strongest inhibitor of UGT1A9-mediated mycophenolic acid glucuronidase activity. Further inhibition kinetic studies using HLMs suggested that ginsenoside Rc competitively and noncompetitively inhibited UGT1A9-mediated propofol and mycophenolic acid glucuronidation activities, with K i values of 2.83 and 3.31 µM, respectively. Next, to investigate whether the inhibitory effect of ginsenoside Rc is specific to the UGT1A9 isoform, we studied the inhibitory potency of ginsenoside Rc on nine human uridine diphospho-glucuronosyltransferase (UGT) activities using recombinant human UGT isoforms. Ginsenoside Rc exhibited a 12.9-fold selectivity (which was similar to niflumic acid at 12.5-fold) for UGT1A9 inhibition. Ginsenoside Rc at 50 µM also inhibited none of the other UGT isoform-specific activities above 12.0%, except for UGT1A9 (>91.5%) in HLMs, indicating that ginsenoside Rc might be used as a selective UGT1A9 inhibitor in reaction phenotyping studies of new chemical entities. Considering lower plasma concentrations (0.01 µM) of ginsenoside Rc in healthy subjects and no induction potential on UGT isoforms, ginsenoside Rc does not cause pharmacokinetic drug interactions with other coadministered drugs metabolized by UGT1A9. SIGNIFICANCE STATEMENT: Ginsenoside Rc selectively inhibited UGT1A9-mediated propofol and mycophenolic acid glucuronidation activities in human liver microsomes and recombinant uridine diphospho-glucuronosyltransferase (UGT) isoforms. It exhibited a 12.9-fold selectivity for UGT1A9 inhibition. Therefore, ginsenoside Rc might be used as a selective UGT1A9 inhibitor in reaction phenotyping studies of new chemical entities, such as niflumic acid.

A Comprehensive In Vivo and In Vitro Assessment of the Drug Interaction Potential of Red Ginseng.

Purpose: Red ginseng is one of the world's most popular herbal medicines; it exhibits a wide range of pharmacologic activities and is often co-ingested with other herbal and conventional medicines. This open-label, randomized, 3-period study investigated the in vivo herb-drug interaction potential for red ginseng extract with cytochrome P-450 (CYP) enzymes and organic anion-transporting polypeptide (OATP) 1B1. METHODS: Fifteen healthy male volunteers (22-28 years; 57.1-80.8 kg) were administered a single dose of cocktail probe substrates (caffeine 100 mg, losartan 50 mg, omeprazole 20 mg, dextromethorphan 30 mg, midazolam 2 mg, and pitavastatin 2 mg) and single or multiple doses of red ginseng extract for 15 days. FINDINGS: The pharmacokinetic profiles of the probe substrates and metabolites after single- or multiple-dose administration of red ginseng extracts were comparable to the corresponding profiles of the control group. The geometric mean ratio of AUC0-t and 90% CIs for the probe substrate drugs between the control and multiple doses of red ginseng for 15 days were within 0.8 to 1.25 (CYP2C9, CYP3A4, and OATP1B1 probe substrates) or slightly higher (CYP1A2, CYP2C19, and CYP2D6 probe substrates). Additional assessments of the in vitro drug interaction potential of red ginseng extracts and the ginsenoside Rb1 on drug-metabolizing enzymes and transporters using human liver microsomes, cryopreserved human hepatocytes, and transporter-overexpressed cells were negative. IMPLICATIONS: Red ginseng poses minimal risks for clinically relevant CYP- or OATP-mediated drug interactions and is well tolerated. Clinical Research Information Service registry no.

Simultaneous Determination of Five Cytochrome P450 Probe Substrates and Their Metabolites and Organic Anion Transporting Polypeptide Probe Substrate in Human Plasma Using Liquid Chromatography-Tandem Mass Spectrometry.

A rapid and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (P450) probe substrates and their phase I metabolites in human plasma was developed. The OATP1B1 (pitavastatin) and five P450 probe substrates, caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A) and their metabolites were extracted from human plasma (50 µL) using methanol. Analytes were separated on a C18 column followed by selected reaction monitoring detection using MS/MS. All analytes were separated simultaneously within a 9 min run time. The developed method was fully validated over the expected clinical concentration range for all analytes tested. The intra- and inter-day precisions for all analytes were lower than 11.3% and 8.82%, respectively, and accuracy was 88.5⁻117.3% and 96.1⁻109.2%, respectively. The lower limit of quantitation was 0.05 ng/mL for dextromethorphan, dextrorphan, midazolam, and 1'-hydroxymidazolam; 0.5 ng/mL for losartan, EXP-3174, omeprazole, 5'-hydroxyomeprazole, and pitavastatin; and 5 ng/mL for caffeine and paraxanthine. The method was successfully used in a pharmacokinetic study in healthy subjects after oral doses of five P450 and OATP1B1 probes. This analytical method provides a simple, sensitive, and accurate tool for the determination of OATP1B1 and five major P450 activities in vivo drug interaction studies.

Acetylshikonin is a novel non-selective cytochrome P450 inhibitor.

Acetylshikonin is a biologically active compound with anti-cancer and anti-inflammatory activity, which is isolated from the roots of Lithospermum erythrorhizoma. An inhibitory effect of acetylshikonin against CYP2J2 activity was discovered recently. Based on this result, this study was expanded to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed a strong inhibitory effect against all P450s tested with IC50 values of 1.4-4.0 µ m. Pre-incubation of acetylshikonin with HLMs and NADPH did not alter the inhibition potency, indicating that acetylshikonin is not a mechanism-based inhibitor. SKF-525A, a widely used non-specific P450 inhibitor, had no inhibitory activity against CYP1A2, 2A6, 2E1 and 2J2, while it showed an inhibitory effect against CYP2B6, CYP2C19 and 2D6 with IC50 values of 2.5, 3.6 and 0.5 µ m, respectively. Our findings indicate that acetylshikonin may be a novel general P450 inhibitor, which could replace SKF-525A.

Inhibitory Effect of Selaginellins from Selaginella tamariscina (Beauv.) Spring against Cytochrome P450 and Uridine 5'-Diphosphoglucuronosyltransferase Isoforms on Human Liver Microsomes.

Selaginella tamariscina (Beauv.) has been used for traditional herbal medicine for treatment of cancer, hepatitis, and diabetes in the Orient. Numerous bioactive compounds including alkaloids, flavonoids, lignans, and selaginellins have been identified in this medicinal plant. Among them, selaginellins having a quinone methide unit and an alkylphenol moiety have been known to possess anticancer, antidiabetic, and neuroprotective activity. Although there have been studies on the biological activities of selaginellins, their modulatory potential of cytochrome P450 (P450) and uridine 5'-diphosphoglucuronosyltransferase (UGT) activities have not been previously evaluated. In this study, we investigated the drug interaction potential of two selaginellins on ten P450 isoforms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2 and 3A) and six UGT isoforms (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using human liver microsomes and liquid chromatography-tandem mass spectrometry. Selaginellin and selaginellin M had high inhibitory potential for CYP2C8-mediated amodiaquine O-demethylation with IC50 values of 0.5 and 0.9 µM, respectively. Selaginellin and selaginellin M also showed medium inhibitory potential against CYP2C9, CYP2J2, UGT1A1, and UGT1A3 (1 µM < IC50 < 5 µM). These two selaginellins had low inhibitory potential against CYP1A2, CYP2A6, CYP2E1, and UGT1A6 (IC50 > 25 µM). This information might be helpful to predict possible drug interaction potential of between selaginellins and co-administered drugs.