LRP1-deficient leptin receptor-positive cells in periodontal ligament tissue reduce alveolar bone mass by inhibiting bone formation.

OBJECTIVE: Leptin receptor-positive (LepR+) periodontal ligament (PDL) cells play a crucial role in osteogenesis during tooth socket healing and orthodontic tooth movement; however, the factors regulating osteoblast differentiation remain unclear. This study aimed to demonstrate the function of low-density lipoprotein receptor-related protein 1 (LRP1) in alveolar bone formation by examining conditional knockout (cKO) mice lacking LRP1 in LepR+ cells. DESIGN: Bone mass and formation were examined via bone morphometric analysis. Bone formation and resorption activities were determined via histochemical staining. Additionally, PDL cells collected from molars were induced to differentiate into osteoblasts with the addition of BMP2 and to mineralize with the addition of osteogenic medium. Osteoblast differentiation of PDL cells was examined by measuring the expression of osteoblast markers. RESULTS: Bone morphometry analysis revealed decreased mineral apposition rate and alveolar bone mass in cKO mice. Additionally, cKO mice showed a decreased number of osterix-positive cells in the PDL. cKO mice had a large number of osteoclasts around the alveolar bone near the root apex and mesial surface of the tooth. In the PDL cells from cKO mice, inhibition of mineralized matrix formation and decreased expression of alkaline phosphatase, osterix, bone sialoprotein, and osteocalcin were observed even when BMP2 was added to the medium. BMP2, BMP4, and osteoprotegerin expression also decreased, but RANKL expression increased dominantly. CONCLUSION: LRP1 in LepR+ cells promotes bone formation by stimulating osteoblast differentiation. Our findings can contribute to clinical research on bone diseases and help elucidate bone metabolism in the periodontal tissue.

Self-assembled GA-Repeated Peptides as a Biomolecular Scaffold for Biosensing with MoS2 Electrochemical Transistors.

Biosensors with two-dimensional materials have gained wide interest due to their high sensitivity. Among them, single-layer MoS2 has become a new class of biosensing platform owing to its semiconducting property. Immobilization of bioprobes directly onto the MoS2 surface with chemical bonding or random physisorption has been widely studied. However, these approaches potentially cause a reduction of conductivity and sensitivity of the biosensor. In this work, we designed peptides that spontaneously align into monomolecular-thick nanostructures on electrochemical MoS2 transistors in a non-covalent fashion and act as a biomolecular scaffold for efficient biosensing. These peptides consist of repeated domains of glycine and alanine in the sequence and form self-assembled structures with sixfold symmetry templated by the lattice of MoS2. We investigated electronic interactions of self-assembled peptides with MoS2 by designing their amino acid sequence with charged amino acids at both ends. Charged amino acids in the sequence showed a correlation with the electrical properties of single-layer MoS2, where negatively charged peptides caused a shift of threshold voltage in MoS2 transistors and neutral and positively charged peptides had no significant effect on the threshold voltage. The transconductance of transistors had no decrease due to the self-assembled peptides, indicating that aligned peptides can act as a biomolecular scaffold without degrading the intrinsic electronic properties for biosensing. We also investigated the impact of peptides on the photoluminescence (PL) of single-layer MoS2 and found that the PL intensity changed sensitively depending on the amino acid sequence of peptides. Finally, we demonstrated a femtomolar-level sensitivity of biosensing using biotinylated peptides to detect streptavidin.

Effect of Robot's Listening Attitude Change on Self-disclosure of the Elderly.

Self-disclosure of life experiences from the viewpoint of integrity is considered beneficial to the psychological health of older adults. It has been shown that people tend to self-disclose more to people they like. Compared to a consistent invariant reward, an improvement in the rewarding behavior of a person has been shown to have a greater positive impact on an individual's liking for the person. Based on these previous studies, we explored the psychological impact of self-disclosure of integrated life experiences on the elderly and the effect of the change in the robot's listening attitude on the elderly's self-disclosure. We conducted an experiment in which 38 elderly participants were asked to self-disclose their life experiences to a robot for approximately 20 min. The participants interacted with either a robot with a consistently positive listening attitude or a robot that initially had a neutral listening attitude that changed to a positive listening attitude. The results showed that self-disclosure of integrated life experiences to the robot had a psychological impact on improving self-esteem. In addition, changes in the robot's listening attitude were found to promote self-disclosure and enhance its impact on self-esteem.

Effect of Multivalency on Phase-Separated Droplets Consisting of Poly(PR) Dipeptide Repeats and RNA at the Solid/Liquid Interface.

Dipeptide repeat proteins (DRPs) are considered a significant cause of amyotrophic lateral sclerosis (ALS), and their liquid-liquid phase separation (LLPS) formation with other biological molecules has been studied both in vitro and in vivo. The immobilization and wetting of the LLPS droplets on glass surfaces are technically crucial for the measurement with optical microscopy. In this work, we characterized the surface diffusion of LLPS droplets of the DRPs with different lengths to investigate the multivalent effect on the interactions of their LLPS droplets with the glass surface. Using fluorescence microscopy and the single-particle tracking method, we observed that the large multivalency drastically changed the surface behavior of the droplets. The coalescence and wetting of the droplets were accelerated by increasing the multivalency of peptides in the LLPS system. Our findings on the effect of multivalency on interactions between droplets and glass surfaces could provide a new insight to enhance the understanding of LLPS formation and biophysical properties related to the solid/liquid interface.

De novo designed peptides form a highly catalytic ordered nanoarchitecture on a graphite surface.

Here we demonstrate that short peptides, de novo designed from first principles, self-assemble on the surface of graphite to produce a highly robust and catalytic nanoarchitecture, which promotes peroxidation reactions with activities that rival those of natural enzymes in both single and multi-substrate reactions. These designable peptides recapitulate the symmetry of the underlying graphite surface and act as molecular scaffolds to immobilize hemin molecules on the electrode in a hierarchical self-assembly manner. The highly ordered and uniform hybrid graphite-peptide-hemin nanoarchitecture shows the highest faradaic efficiency of any hybrid electrode reported. Given the explosive growth of the types of chemical reactions promoted by self-assembled peptide materials, this new approach to creating complex electrocatalytic assemblies will yield highly efficient and practically applicable electrocatalysts.

p53 deficiency promotes bone regeneration by functional regulation of mesenchymal stromal cells and osteoblasts.

INTRODUCTION: The detailed mechanism of the process during bone healing of drill-hole injury has been elucidated, but a crucial factor in regulating drill-hole healing has not been identified. The transcription factor p53 suppresses osteoblast differentiation through inhibition of osterix expression. In present study, we demonstrate the effects of p53 deficiency on the capacity of MSCs and osteoblasts during drill-hole healing. MATERIALS AND METHODS: Mesenchymal stromal cells (MSCs) and osteoblasts were collected from bone marrow and calvaria of p53 knockout (KO) mice, respectively. The activities of cell mobility, cell proliferation, osteoblast differentiation, and wound healing of MSCs and/or osteoblasts were determined by in vitro experiments. In addition, bone healing of drill-hole injury in KO mice was examined by micro-CT and immunohistological analysis using anti-osterix, Runx2, and sclerostin antibodies. RESULTS: KO MSCs stimulated cell mobility, cell proliferation, and osteoblast differentiation. Likewise, KO osteoblasts enhanced cell proliferation and wound healing. KO MSCs and osteoblasts showed high potency in the inflammation and callus formation phases compared to those from wild-type (WT) mice. In addition, increased expression of osterix and Runx2 was observed in KO MSCs and osteoblasts that migrated in the drill-hole. Conversely, sclerostin expression was inhibited in KO mice. Eventually, KO mice exhibited high repairability of drill-hole injury, suggesting a novel role of p53 in MSCs and osteoblasts in improving bone healing. CONCLUSION: p53 Deficiency promotes bone healing of drill-hole injury by enhancing the bone-regenerative ability of MSCs and osteoblasts.

Age dependence of the maturation of the midpalatal suture in the stability of orthodontic anchoring screws.

INTRODUCTION: Orthodontic anchoring screws (OASs) have been placed around midpalatal sutures in patients of various ages. Our previous study found that OAS placement more than 1.5 mm from midpalatal suture was more successful than placement directly at the suture. This study aimed to investigate the relationship between age and midpalatal suture maturation, considering factors affecting the failure of OASs using cone-beam computed tomography. METHODS: In total, 150 patients who underwent cone-beam computed tomography were selected. The total depth and sutured depth of the midpalatal suture corresponding area to anterior (interpremolar zone) and posterior region (mesial and distal borders of the first molar) were measured, and the ratio of sutured depth to total depth (sutured ratio) was calculated. RESULTS: The mean sutured ratios at interpremolar zone and mesial and distal borders of the first molar according to age were 40%, 60%, and 63% in the younger group (≤17 years), 46%, 76%, and 76% in the middle group (18-25 years), and 47%, 74%, and 76% in the older group (≥26 years), respectively. The sutured ratio of the anterior region was significantly lower than that of the posterior region (P <0.01). Each mean sutured ratio of the middle and older group was significantly higher than that of the younger group on both sides (P <0.01). According to the cervical vertebral maturation, the mean sutured ratio of cervical vertebral stages 5-6 was significantly higher than cervical vertebral stages 1-3 on the distal side (P <0.05). CONCLUSIONS: Incomplete closure of the midpalatal suture was observed frequently, even in the older group. This might be caused by insufficient calcification of the midpalatal suture, including in elder patients. To prevent OAS placement to the unsutured area, the midpalatal suture should be avoided regardless of age.

Influence of pre-drilling diameter on the stability of orthodontic anchoring screws in the mid-palatal area.

PURPOSE: The aim of this study was to investigate the stability of orthodontic anchor screws (OASs) in the mid-palatal area according to pre-drilling diameter. METHODS: The success rate of 161 OASs (83 patients, φ2.0 mm, 6.0 mm in length) placed in a corresponding area to the mesial and distal borders of the first molar (mesial zone and distal zone) was assessed according to placement location and pre-drilling diameter (1.2 and 1.5 mm). Placement torque values from 73 OASs with a pre-drilling diameter of 1.2 mm were compared between success and failure groups. RESULTS: The success rates of OASs pre-drilled with φ1.2 and 1.5 mm were 94.5% and 83.0%, respectively (P < 0.05); corresponding rates in the mesial zone were 100.0% and 77.3% (P < 0.005), and those in the distal zone were 89.2% and 88.6%, respectively. Placement torques of OASs predrilled with φ1.2 mm in the success and failure groups were 25.9 and 19.2 N·cm, respectively (P < 0.05). CONCLUSION: A smaller pre-drilling diameter was associated with a higher success rate of OASs in the mid-palatal area, especially in the mesial zone. When pre-drilling diameter of 1.2 mm was used for φ2.0 mm OAS, greater placement torque was indicative of greater OAS stability.

Diffusion of LLPS Droplets Consisting of Poly(PR) Dipeptide Repeats and RNA on Chemically Modified Glass Surface.

The liquid-liquid phase separation (LLPS) of proteins and RNA molecules has emerged in recent years as an important physicochemical process to explain the organization of membrane-less organelles in living cells and cellular functions and even some fatal neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS) due to the spontaneous condensation and growth of LLPS droplets. In general, the characterization of LLPS droplets has been performed by optical microscopy, where we need transparent substrates. By virtue of the liquid and wetting properties of LLPS droplets on a glass surface, there have been some technical protocols recommended to immobilize droplets on the surfaces. However, interactions between LLPS droplets and glass surfaces still remain unclear. Here, we investigated the surface diffusion of LLPS droplets on the glass surface to understand the interactions of droplets in a dynamic manner, and employed chemically modified glass surface with charges to investigate their Coulombic interaction with the surface. Using the single-particle tracking method, we first analyzed the diffusion of droplets on an untreated glass surface. Then, we compared the diffusion modes of LLPS droplets on each substrate and found that there were two major states of droplets on a solid surface: fix and diffusion mode for the LLPS droplet diffusion. While untreated glass showed a diffusion of droplets mainly, chemically modified glass with positive charges exhibited droplets fixed on the surface. It could arise from the Coulombic interaction between droplets and solid surface, where LLPS droplets have a negative ζ-potential. Our findings on the dynamics of LLPS at the solid/liquid interface could provide a novel insight to advance fundamental studies for understanding the LLPS formation.

Aqueous synthesis of tin- and indium-doped WO3 films via evaporation-driven deposition and their electrochromic properties.

M-doped WO3 (M = Sn or In) films were prepared from aqueous coating solutions via evaporation-driven deposition during low-speed dip coating. Sn- and In-doping were easily achieved by controlling the chemical composition of simple coating solutions containing only metal salts and water. The crystallinity of the WO3, Sn-doped WO3, and In-doped WO3 films varied with heating temperature, where amorphous and crystalline films were obtained by heating at 200 and 500 °C, respectively. All the amorphous and crystalline films showed an electrochromic response, but good photoelectrochemical stability was observed only for the crystalline samples heated at 500 °C. The crystalline In-WO3 films exhibited a faster electrochromic color change than the WO3 or Sn-WO3 films, and good cycle stability for the electrochromic response in the visible wavelength region.

Plaque-removal effect of ultrafine bubble water: Oral application in patients undergoing orthodontic treatment.

During orthodontic treatment, plaque tends to form around fixed orthodontic appliances, which increases the risk of dental caries. It has been reported that ultarafine bubble with a diameter <1 µm water (UFBW) effectively removes organic matter. In addition, UFBW is harmless and stable for at least one month with refrigeration. The aim of this study was to examine the plaque-removal effect of ultrafine bubble water (UFBW) to establish a new method to prevent dental caries in patients during orthodontic treatment procedures. The in vitro study examined different concentrations of UFBW and compared the cleaning effect to that of existing mouthwashes. High-concentration UFBW (HUFBW) was most effective in cleaning. In the subsequent clinical study, HUFBW showed a significantly higher plaque-removal effect compared to distilled water (p<0.01). Thus, supplementary use of HUFBW could decrease the incidence of dental caries during orthodontic treatment.

Bach1 Inhibition Suppresses Osteoclastogenesis via Reduction of the Signaling via Reactive Oxygen Species by Reinforced Antioxidation.

Bone destructive diseases such as periodontitis are common worldwide and are caused by excessive osteoclast formation and activation. Receptor activator of nuclear factor-κB ligand (RANKL) is essential factor for osteoclastogenesis. This triggers reactive oxygen species (ROS), which has a key role in intracellular signaling as well exerting cytotoxicity. Cells have protective mechanisms against ROS, such as nuclear factor E2-related factor 2 (Nrf2), which controls the expression of many antioxidant enzyme genes. Conversely, BTB and CNC homology 1 (Bach1), a competitor for Nrf2, transcriptionally represses the expression of anti-oxidant enzymes. Previously, we demonstrated that RANKL induces Bach1 nuclear import and attenuates the expression of Nrf2-mediated antioxidant enzymes, thereby augmenting intracellular ROS signaling and osteoclastogenesis. However, it remains unknown if Bach1 inhibitors attenuate osteoclastogenesis. In this study, we hypothesized that Bach1 inhibition would exert an anti-osteoclastogenic effects via diminishing of intracellular ROS signaling through augmented antioxidation. We used RAW 264.7 cells as osteoclast progenitor cells. Using flow cytometry, we found that Bach1 inhibitors attenuated RANKL-mediated ROS generation, which resulted in the inhibition of osteoclastogenesis. Local injection of a Bach1 inhibitor into the calvaria of male BALB/c mice blocked bone destruction induced by lipopolysaccharide. In conclusion, we demonstrate that Bach1 inhibitor attenuates RANKL-mediated osteoclastogenesis and bone destruction in mice by inducing the expression of Nrf2-regulated antioxidant enzymes that consequently decrease intracellular ROS levels. Bach1 inhibitors have potential in inhibiting bone destructive diseases such as periodontitis, rheumatoid arthritis and osteoporosis.

Effects of occlusal disharmony on cardiac fibrosis, myocyte apoptosis and myocyte oxidative DNA damage in mice.

Occlusal disharmony leads to morphological changes in the hippocampus and osteopenia of the lumbar vertebra and long bones in mice, and causes stress. Various types of stress are associated with increased incidence of cardiovascular disease, but the relationship between occlusal disharmony and cardiovascular disease remain poorly understood. Therefore, in this work, we examined the effects of occlusal disharmony on cardiac homeostasis in bite-opening (BO) mice, in which a 0.7 mm space was introduced by cementing a suitable applicance onto the mandibular incisior. We first examined the effects of BO on the level of serum corticosterone, a key biomarker for stress, and on heart rate variability at 14 days after BO treatment, compared with baseline. BO treatment increased serum corticosterone levels by approximately 3.6-fold and the low frequency/high frequency ratio, an index of sympathetic nervous activity, was significantly increased by approximately 4-fold by the BO treatment. We then examined the effects of BO treatment on cardiac homeostasis in mice treated or not treated with the non-selective ß-blocker propranolol for 2 weeks. Cardiac function was significantly decreased in the BO group compared to the control group, but propranolol ameliorated the dysfunction. Cardiac fibrosis, myocyte apoptosis and myocyte oxidative DNA damage were significantly increased in the BO group, but propranolol blocked these changes. The BO-induced cardiac dysfunction was associated with increased phospholamban phosphorylation at threonine-17 and serine-16, as well as inhibition of Akt/mTOR signaling and autophagic flux. These data suggest that occlusal disharmony might affect cardiac homeostasis via alteration of the autonomic nervous system.

Low-intensity pulsed ultrasound enhances the rate of lateral tooth movement and compensatory bone formation in rats.

INTRODUCTION: Because mechanical stimulation of the periodontal ligament by low-intensity pulsed ultrasound (LIPUS) has been shown to increase the speed of bone remodeling, this study aimed to examine the effects of LIPUS stimulation on the rate of tooth movement and bone remodeling during lateral tooth movement. METHODS: Twelve-week-old Wistar rats were divided into 2 groups. The LIPUS group received experimental tooth movement with LIPUS stimulation, and the tooth movement (TM) group were provided experimental tooth movement without LIPUS. For each group, the upper right first molars were moved buccally with fixed appliances. LIPUS exposure was placed in the region corresponding to the right maxillary first molar. Three days after tooth movement, tartrate-resistant acid phosphatase was examined. Fourteen days after tooth movement, the intermolar width, bone mineral content, and bone volume fraction were analyzed by micro-computed tomography, and newly formed bone was measured histomorphometrically. RESULTS: The number of TRAP-positive cells in the compressed region was higher in the LIPUS group. The intermolar width was significantly higher in the LIPUS group than in the TM group. The alveolar bone around the maxillary first molar showed no differences in bone mineral content and bone volume fraction between the LIPUS and TM groups. The LIPUS group exhibited a more significant amount of newly formed alveolar bone than the TM group. CONCLUSIONS: The present study provides evidence of the beneficial effects of LIPUS on the lateral tooth movement.

Mandibular prognathism attenuates brain blood flow induced by chewing.

Mastication is closely related to brain function. Animal experiments have revealed that tooth loss has a negative influence on brain function. Clinical studies also suggest that normal occlusion is an essential factor for favorable brain function. Mandibular prognathism (MP) usually results in occlusal dysfunction. However, the relationship between MP and brain function remains unclear. In the present study, we examined the relationship between MP and brain function by measuring brain blood flow (BBF). Seventeen subjects with normal occlusion (NORM) and 25 patients with MP participated in this study. The number of occlusal contacts were counted. Electromyography of the masseter muscles during clenching was also recorded. BBF was measured with non-invasive functional near-infrared spectroscopy during calculation task and chewing task. The number of the occlusal contacts and masseter muscle activity were lower in MP compared with NORM. The calculation task increased BBF in both groups. The chewing task also increased BBF in the inferior frontal gyrus in both groups, although the increase in MP was smaller than in NORM. We discovered that patients with MP exhibited a smaller increase in BBF at the inferior frontal gyrus during chewing as compared with NORM. As such, MP would negatively affect brain function.

[Challenges Faced by the Palliative Care Team in Treating Breast Cancer Outpatients with Chemotherapy].

In this study, we examined 239 outpatients receiving chemotherapy for breast cancer for a period of 6 months from July 2016 to December 2016. Using a questionnaire, we investigated the patients' symptom score and uneasiness. A symptom score of 2 and over was found in 24.7%(59)of the cases. Twenty-seven of the 59 cases experienced adverse effects of chemotherapy. Peripheral neuropathy was observed in 20 cases, of which only 2 cases improved after providing palliative care. Palliative care was effective against nausea, constipation, malaise, and sleeping disorders. Thirty-two cases(13.4%)had 5 or more painful feeling score. Among these, 10 cases resulted from the adverse effects of treatment, 10 cases from the aggravation of existing cancer, and 6 cases showed anxiety for the illness, family, and future. In 15 of the 32 cases, the pain score improved by providing palliative care, conversation with the nursing staff, reduction in the quantity of drug intake, etc.

Pharmacological evaluation of TAK-828F, a novel orally available RORγt inverse agonist, on murine chronic experimental autoimmune encephalomyelitis model.

We investigated the potency of TAK-828F, a RORγt inverse agonist, in murine experimental autoimmune encephalomyelitis (EAE) model. TAK-828F inhibited the differentiation of Th17 and Th1/17 cells in inguinal lymph node. Increase of these cells in central nervous system (CNS) was also inhibited by TAK-828F. Prophylactic and therapeutic treatments of TAK-828F were efficacious in the model. Plasma concentration of TAK-828F was higher than that in CNS. These results indicate that TAK-828F mainly acts at peripheral and results in the reduction of Th17- and Th1/17-dependent inflammation in CNS. Blocking RORγt may be a promising strategy for treatment of multiple sclerosis.

Compression and tension variably alter Osteoprotegerin expression via miR-3198 in periodontal ligament cells.

BACKGROUND: Osteoclasts play a critical role in bone resorption due to orthodontic tooth movement (OTM). In OTM, a force is exerted on the tooth, creating compression of the periodontal ligament (PDL) on one side of the tooth, and tension on the other side. In response to these mechanical stresses, the balance of receptor activator of nuclear-factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) shifts to stimulate osteoclastogenesis. However, the mechanism of OPG expression in PDL cells under different mechanical stresses remains unclear. We hypothesized that compression and tension induce different microRNA (miRNA) expression profiles, which account for the difference in OPG expression in PDL cells. To study miRNA expression profiles resulting from OTM, compression force (2 g/cm2) or tension force (15% elongation) was applied to immortalized human PDL (HPL) cells for 24 h, and miRNA extracted. The miRNA expression in each sample was analyzed using a human miRNA microarray, and the changes of miRNA expression were confirmed by real-time RT-PCR. In addition, miR-3198 mimic and inhibitor were transfected into HPL cells, and OPG expression and production assessed. RESULTS: We found that certain miRNAs were expressed differentially under compression and tension. For instance, we observed that miR-572, - 663, - 575, - 3679-5p, UL70-3p, and - 3198 were upregulated only by compression. Real-time RT-PCR confirmed that compression induced miR-3198 expression, but tension reduced it, in HPL cells. Consistent with previous reports, OPG expression was reduced by compression and induced by tension, though RANKL was induced by both compression and tension. OPG expression was upregulated by miR-3198 inhibitor, and was reduced by miR-3198 mimic, in HPL cells. We observed that miR-3198 inhibitor rescued the compression-mediated downregulation of OPG. On the other hand, miR-3198 mimic reduced OPG expression under tension. However, RANKL expression was not affected by miR-3198 inhibitor or mimic. CONCLUSIONS: We conclude that miR-3198 is upregulated by compression and is downregulated by tension, suggesting that miR-3198 downregulates OPG expression in response to mechanical stress.

Role of ß-adrenergic signaling in masseter muscle.

In skeletal muscle, the major isoform of ß-adrenergic receptor (ß-AR) is ß2-AR and the minor isoform is ß1-AR, which is opposite to the situation in cardiac muscle. Despite extensive studies in cardiac muscle, the physiological roles of the ß-AR subtypes in skeletal muscle are not fully understood. Therefore, in this work, we compared the effects of chronic ß1- or ß2-AR activation with a specific ß1-AR agonist, dobutamine (DOB), or a specific ß2-AR agonist, clenbuterol (CB), on masseter and cardiac muscles in mice. In cardiac muscle, chronic ß1-AR stimulation induced cardiac hypertrophy, fibrosis and myocyte apoptosis, whereas chronic ß2-AR stimulation induced cardiac hypertrophy without histological abnormalities. In masseter muscle, however, chronic ß1-AR stimulation did not induce muscle hypertrophy, but did induce fibrosis and apoptosis concomitantly with increased levels of p44/42 MAPK (ERK1/2) (Thr-202/Tyr-204), calmodulin kinase II (Thr-286) and mammalian target of rapamycin (mTOR) (Ser-2481) phosphorylation. On the other hand, chronic ß2-AR stimulation in masseter muscle induced muscle hypertrophy without histological abnormalities, as in the case of cardiac muscle, concomitantly with phosphorylation of Akt (Ser-473) and mTOR (Ser-2448) and increased expression of microtubule-associated protein light chain 3-II, an autophagosome marker. These results suggest that the ß1-AR pathway is deleterious and the ß2-AR is protective in masseter muscle. These data should be helpful in developing pharmacological approaches for the treatment of skeletal muscle wasting and weakness.

Pharmacological effects of TAK-828F: an orally available RORγt inverse agonist, in mouse colitis model and human blood cells of inflammatory bowel disease.

OBJECTIVE AND DESIGN: To evaluate the potency of RORγt blockade for treatment of Inflammatory Bowel Disease (IBD), the efficacy of TAK-828F, a novel RORγt inverse agonist, in anti-TNF-α mAb non-responsive mouse colitis model and effect of TAK-828F on IL-17 production in peripheral mononuclear blood cells (PBMCs) of anti-TNF-α naive and treatment-failure patients of IBD was investigated. METHODS AND RESULTS: The colitis model showed Th17-dependent pathogenicity and response to anti-IL-12/23p40 monoclonal antibody (mAb), but no response to anti-TNF-α mAb. In the model, TAK-828F, at oral dosages of 1 and 3 mg/kg, inhibited progression of colitis and reduced the immune reaction that characterize Th17 cells. Anti-IL-17A mAb showed neither efficacy nor change in the T cell population and colonic gene expression in the model. In the normal mouse, a 4-week treatment of TAK-828F at 30 mg/kg did not severely reduce lymphocyte cell counts in peripheral and intestinal mucosa, which was observed in RORγ-/- mice. TAK-828F strongly inhibited IL-17 gene expression with IC50 values from 21.4 to 34.4 nmol/L in PBMCs from anti-TNF mAb naive and treatment-failure patients of IBD. CONCLUSIONS: These results indicate that RORγt blockade would provide an effective approach for treating refractory patients with IBD by blocking IL-23/Th17 pathway.