Adiponectin-Receptor Agonistic Dipeptide Tyr-Pro Stimulates the Acetylcholine Nervous System in NE-4C Cells.

The dipeptide Tyr-Pro has physiological potential for intact transportability into the brain parenchyma, prevention of cognitive impairment, and an adiponectin receptor 1 (AdipoR1) agonistic effect. The present study aimed to understand the effect of Tyr-Pro on the acetylcholine (ACh) nervous system and its underlying mechanism in NE-4C nerve cells. Concentration-dependent ACh production was induced by stimulation with Tyr-Pro and AdipoRon (an AdipoR1 agonist), along with the expression of AdipoR1 and choline acetyltransferase (ChAT) in NE-4C cells. By knocking down AdipoR1 in the cells, Tyr-Pro promoted ChAT expression, along with the activations of AMPK and ERK 1/2. Tyr-Pro did not alter acetylcholinesterase or ACh receptors, indicating that the dipeptide might operate as an ACh accelerator in nerve cells. This study provides the first evidence that the AdipoR1 agonistic Tyr-Pro is a promising dipeptide responsible for the stimulation of the ACh nervous system by AdipoR1-induced ChAT activation.

Effect of Devised Simultaneous Physical Function Improvement Training and Posture Learning Exercises on Posture.

Poor posture in young adults and middle-aged people is associated with neck and back pain which are among the leading causes of disability worldwide. Training posture maintenance muscles and learning about ideal posture are important for improving poor posture. However, the effect of using both approaches simultaneously has not been verified, and it is unclear how long the effects persist after the intervention. Forty female university students were randomly and evenly assigned to four groups: physical function improvement training, posture learning, combination, and control groups. Four weeks of intervention training was conducted. Postural alignment parameters were obtained, including trunk anteroposterior inclination, pelvic anteroposterior inclination, and vertebral kyphosis angle. Physical function improvement training for improving crossed syndrome included two types of exercises: "wall-side squatting" and "wall-side stretching". The posture learning intervention consisted of two types of interventions: "standing upright with their back against the wall" and "rolled towel". A multiple comparison test was performed after analysis of covariance to evaluate the effect of each group's postural change intervention on postural alignment. Only the combination group showed an effective improvement in all posture alignments. However, it was found that a week after the 4-week intervention, the subjects' postures returned to their original state.

A novel device for lower leg intermittent pneumatic compression synchronized with active ankle exercise for prevention of deep vein thrombosis.

OBJECTIVE: Intermittent pneumatic compression devices (IPCDs) and active ankle exercises have been shown to be efficacious in preventing venous thromboembolism (VTE) by increasing venous flow velocity and volume. However, IPCDs are expensive and require electricity; therefore, they cannot be used in the event of power loss. We developed a non-powered device that provides lower leg intermittent pneumatic compression synchronized with AAEs (LISA) and compared its efficacy with AAEs alone in increasing the peak velocity in the femoral vein. METHODS: The study population consisted of 20 healthy younger men and 20 healthy older men who performed AAE every 2 s in a sitting posture under four conditions: AAE with LISA (AAE+LISA), AAE alone (AAE), AAE with IPCD, and AAE with a graduated compression stocking. RESULTS: The PVs under all conditions were significantly higher than those at rest. The PVs in the AAE+LISA condition were significantly higher than those in the AAE alone condition in both younger and older groups (both p < .001). CONCLUSIONS: AAE with LISA significantly increased the PV, suggesting that LISA might be useful for preventing DVT.

In vitro and in silico characterization of adiponectin-receptor agonist dipeptides.

The aim of this study is to develop a dipeptide showing an adiponectin receptor 1 (AdipoR1) agonistic effect in skeletal muscle L6 myotubes. Based on the structure of the AdipoR1 agonist, AdipoRon, 15 synthetic dipeptides were targeted to promote glucose uptake in L6 myotubes. Tyr-Pro showed a significant increase in glucose uptake among the dipeptides, while other dipeptides, including Pro-Tyr, failed to exert this effect. Tyr-Pro induces glucose transporter 4 (Glut4) expression in the plasma membrane, along with adenosine monophosphate-activated protein kinase (AMPK) activation. In AdipoR1-knocked down cells, the promotion by Tyr-Pro was ameliorated, indicating that Tyr-Pro may directly interact with AdipoR1 as an agonist, followed by the activation of AMPK/Glut4 translocation in L6 myotubes. Molecular dynamics simulations revealed that a Tyr-Pro molecule was stably positioned in the two potential binding pockets (sites 1 and 2) of the seven-transmembrane receptor, AdipoR1, anchored in a virtual 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane. In conclusion, we demonstrated the antidiabetic function of the Tyr-Pro dipeptide as a possible AdipoR1 agonist.

Effects of intermittent pneumatic compression on femoral vein peak venous velocity during active ankle exercise.

INTRODUCTION: The risk of developing deep vein thrombosis (DVT) is high even after the period of bed rest following major general surgery including total joint arthroplasty (TJA). Mobile intermittent pneumatic compression (IPC) devices allow the application of IPC during postoperative exercise. Although ambulation included ankle movement, no reports have been made regarding the effects of IPC during exercise, including active ankle exercise (AAE), on venous flow. This study was performed to examine whether using a mobile IPC device can effectively augment the AAE-induced increase in peak velocity (PV). METHODS: PV was measured by Doppler ultrasonography in the superficial femoral vein at rest, during AAE alone, during IPC alone, and during AAE with IPC in 20 healthy subjects in the sitting position. PV in AAE with IPC was measured with a mobile IPC device during AAE in the strong compression phase. AAE was interrupted from the end of the strong compression phase to minimize lower limb fatigue. RESULTS: AAE with IPC (76.2 cm/s [95%CI, 69.0-83.4]) resulted in a significant increase in PV compared to either AAE or IPC alone (47.1 cm/s [95%CI, 38.7-55.6], p < 0.001 and 48.1 cm/s [95%CI, 43.7-52.4], p < 0.001, respectively). DISCUSSION: Reduced calf muscle pump activity due to the decline in ambulation ability reduced venous flow. Therefore, use of a mobile IPC device during postoperative rehabilitation in hospital and activity including self-training in an inpatient ward may promote venous flow compared to postoperative exercise without IPC. CONCLUSION: Use of a mobile IPC device significantly increased the PV during AAE, and simultaneous AAE with IPC could be useful evidence for the prevention of DVT in clinical settings, including after TJA.

Reactive pericytes in early phase are involved in glial activation and late-onset hypersusceptibility to pilocarpine-induced seizures in traumatic brain injury model mice.

In this study, among neurovascular unit (NVU) cells, we focused on pericyte reactivity in mice subjected to controlled cortical impact (CCI) to understand how traumatic brain injury (TBI) causes uncoordinated crosstalk in the NVU and alters neuronal activity. Histological analyses of brain pericytes, microglia and astrocytes were performed for up to 28 days after CCI in the injured ipsilateral hippocampus. To evaluate altered neuronal activity caused by CCI, we measured seizure susceptibility to a sub-threshold dose of pilocarpine on postoperative day 7, 14, 21 and 28. Platelet-derived growth factor receptor (PDGFR) ß immunoreactivity in pericytes significantly increased from 1 h to 4 days after CCI. The expression of Iba1 and GFAP, as markers of microglia and astrocytes, respectively, increased from 4 to 28 days after CCI. The severity of seizure induced by pilocarpine gradually increased, becoming significant at 28 days after CCI. Then, we treated CCI mice with an inhibitor of PDGFR signaling, imatinib, during the postoperative day 0-4 period. Imatinib lowered seizure susceptibility to pilocarpine and suppressed microglial activation in the injured hippocampus at postoperative day 28. These findings indicate that brain pericytes with rapidly increased PDGFRß expression may drive TBI-induced dysregulation of NVU function and brain hyperexcitability.

A portable pneumatic compression device to prevent venous thromboembolism in orthopedic patients with the highest risks of both venous thrombosis and bleeding: A case series study.

PURPOSE: There is a pressing need for safe venous thromboembolism (VTE) prophylaxis in orthopedic patients with the highest risks of both venous thrombosis and bleeding. Portable intermittent pneumatic compression device (IPCD) has proven to be effective and safe in patients with a high risk of venous thrombosis and low bleeding risk. Therefore, this study examined the effectiveness, safety, and wearing compliance of portable IPCD for postoperative VTE prophylaxis in patients with the highest risks of both venous thrombosis and bleeding. METHODS: The cases consisted of 38 patients who had used a portable IPCD and had the highest risks of both venous thrombosis and bleeding. We examined the incidence of VTE to assess the effectiveness of the portable IPCD, the presence of hemorrhagic adverse events to assess safety, and the wearing rate to assess wearing compliance. RESULTS: The incidences of asymptomatic and symptomatic deep vein thrombosis were 5.3% and 2.6%, respectively. The incidence of hemorrhagic adverse events was 21.1% in patients who received anticoagulants and wore an IPCD simultaneously and 0% in patients who wore an IPCD but did not receive anticoagulants. The wearing rate (i.e. ≥18 h/day) was 100%. CONCLUSION: Portable IPCD has the potential for safe VTE prophylaxis in patients at high risks for both venous thrombosis and bleeding. Therefore, we suggest that such patients use a portable IPCD for VTE prophylaxis.

Oncostatin-M-Reactive Pericytes Aggravate Blood-Brain Barrier Dysfunction by Activating JAK/STAT3 Signaling In Vitro.

Oncostatin M (OSM) is a cytokine of the interleukin (IL)-6 family members. It induces blood-brain barrier (BBB) dysfunction by activating Janus-activated kinase (JAK) and signal transducer and activator of transcription (STAT) 3 pathways in brain endothelial cells. Brain pericytes located around microvessels are one of the BBB constituents. Pericytes work as a boundary surface between the blood circulation and brain parenchyma, and their functions are altered under pathophysiological conditions, leading to BBB dysregulation. However, it remains unknown whether pericytes are associated with OSM-induced BBB dysfunction. We demonstrated that pericyte exposure to OSM (100 ng/mL) elevated phosphorylation of STAT3, a main OSM signaling pathway, and that pericytes expressed OSM receptors (OSMRs) including OSMRß and glycoprotein 130. These results suggest that pericytes are able to respond to OSM. To determine the effects of OSM-reactive pericytes on BBB functions, rat brain endothelial cell (RBEC) monolayers were cultured with OSM-treated pericytes. The presence of pericytes exposed to 100 ng/mL of OSM for 48 h aggravated both the elevated permeability to sodium fluorescein and the lowered transendothelial electrical resistance which were induced by OSM in RBECs. This OSM-reactive pericyte-induced aggravation of lowered RBEC barrier function was reversed by ruxolitinib, a JAK inhibitor. These findings suggest that activated JAK/STAT3 signaling in pericytes contributes to OSM-produced BBB breakdown. Thus, OSM-reactive pericytes may have to be considered a characteristic machinery in the formation and progression of BBB breakdown under pathological conditions associated with increased OSM levels.

"Cation-Stitching Cascade": exquisite control of terpene cyclization in cyclooctatin biosynthesis.

Terpene cyclization is orchestrated by terpene cyclases, which are involved in the biosynthesis of various cyclic natural products, but understanding the origin and mechanism of the selectivity of terpene cyclization is challenging. In this work, we describe an in-depth mechanistic study on cyclooctatin biosynthesis by means of theoretical calculations combined with experimental methods. We show that the main framework of cyclooctatin is formed through domino-type carbocation transportation along the terpene chain, which we call a "cation-stitching cascade", including multiple hydrogen-shifts and a ring rearrangement that elegantly determine the stereoselectivity.

Synthesis of large [2]rotaxanes. The relationship between the size of the blocking group and the stability of the rotaxane.

[2]Rotaxanes with large macrocyclic phenanthrolines were prepared by the template method, and the stability of the rotaxanes was examined. Compared to the tris(biphenyl)methyl group, the tris(4-cyclohexylbiphenyl)methyl group was a larger blocking group, and the rate of the dissociation of the components decreased significantly when the thermal stability of a rotaxane with a 41-memebered ring was examined. We also succeeded in the synthesis of larger rotaxanes by the oxidative dimerization of alkynes with these bulky blocking groups, utilizing the catalytic activity of the macrocyclic phenanthroline-Cu complex.