Mast cells (MCs) are systemically distributed and secrete several allergic mediators such as histamine and leukotrienes to cause type I hypersensitivity. Dasatinib is a type of anti-cancer agent and it has also been reported to inhibit human basophils. However, dasatinib has not been reported for its inhibitory effects on MCs or type I hypersensitivity in mice. In this study, we examined the inhibitory effect of dasatinib on MCs and MC-mediated allergic response in vitro and in vivo. In vitro, dasatinib inhibited the degranulation of MCs by antigen stimulation in a dose-dependent manner (IC 50 , ~34 nM for RBL-2H3 cells; ~52 nM for BMMCs) without any cytotoxicity. It also suppressed the secretion of inflammatory cytokines IL-4 and TNF-α by antigen stimulation. Furthermore, dasatinib inhibited MC-mediated passive cutaneous anaphylaxis (PCA) in mice (ED 50 , ~29 mg/kg). Notably, dasatinib significantly suppressed the degranulation of MCs in the ear tissue. As the mechanism of its effect, dasatinib inhibited the activation of Syk and Syk-mediated downstream signaling proteins, LAT, PLCγ1, and three typical MAP kinases (Erk1/2, JNK, and p38), which are essential for the activation of MCs. Interestingly, in vitro tyrosine kinase assay, dasatinib directly inhibited the activities of Lyn and Fyn, the upstream tyrosine kinases of Syk in MCs. Taken together, dasatinib suppresses MCs and PCA in vitro and in vivo through the inhibition of Lyn and Fyn Src-family kinases. Therefore, we suggest the possibility of repositioning the anti-cancer drug dasatinib as a treatment for various MC-mediated type I hypersensitive diseases.

BACKGROUND: Controlled hypotension (CH) provides a better surgical environment and reduces operative time. However, there are some risks related to organ hypoperfusion. The EV1000/FloTrac system can provide continuous cardiac output monitoring without the insertion of pulmonary arterial catheter. The present study investigated the efficacy of this device in double jaw surgery under CH.METHODS: We retrospectively reviewed the medical records of patients who underwent double jaw surgery between 2010 and 2015. Patients were administered conventional general anesthesia with desflurane; CH was performed with remifentanil infusion and monitored with an invasive radial arterial pressure monitor or the EV1000/FloTrac system. We allocated the patients into two groups, namely an A-line group and an EV1000 group, according to the monitoring methods used, and the study variables were compared.RESULTS: Eighty-five patients were reviewed. The A-line group reported a higher number of failed CH (P = 0.005). A significant correlation was found between preoperative hemoglobin and intraoperative packed red blood cell transfusion (r = 0.525; P < 0.001). In the EV1000 group, the mean arterial pressure (MAP) was significantly lower 2 h after CH (P = 0.014), and the cardiac index significantly decreased 1 h after CH (P = 0.001) and 2 h after CH (P = 0.007). Moreover, venous oxygen saturation (ScVO2) decreased significantly at both 1 h (P = 0.002) and 2 h after CH (P = 0.029); however, these values were within normal limits.CONCLUSION: The EV1000 group reported a lower failure rate of CH than the A-line group. However, EV1000/FloTrac monitoring did not present with any specific advantage over the conventional arterial line monitoring when CH was performed with the same protocol and same mean blood pressure. Preoperative anemia treatment will be helpful to decrease intraoperative transfusion. Furthermore, ScVO2 monitoring did not present with sufficient benefits over the risk and cost.
Anemia ; Anesthesia, General ; Arterial Pressure ; Blood Pressure ; Cardiac Output ; Catheters ; Erythrocyte Transfusion ; Humans ; Hypotension, Controlled ; Medical Records ; Operative Time ; Orthognathic Surgery ; Osteotomy, Le Fort ; Oxygen ; Retrospective Studies ; Vascular Access Devices

Mast cells are the most prominent effector cells of Type 1 hypersensitivity immune responses. CYC116 [4-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-[4-(morpholin-4-yl)phenyl] pyrimidin-2-amine] is under development to be used as an anti-cancer drug, but the inhibitory effects of CYC116 on the activation of mast cells and related allergy diseases have not reported as of yet. In this study, we demonstrated, for the first time, that CYC116 inhibited the degranulation of mast cells by antigen stimulation (IC₅₀, ∼1.42 µM). CYC116 also inhibited the secretion of pro-inflammatory cytokines including TNF-α (IC₅₀, ∼1.10 µM), and IL-6 (IC₅₀, ∼1.24 µM). CYC116 inhibited the mast cell-mediated allergic responses, passive cutaneous anaphylaxis (ED50, ∼22.5 mg/kg), and passive systemic anaphylaxis in a dose-dependent manner in laboratory experiments performed on mice. Specifically, CYC116 inhibited the activity of Fyn in mast cells and inhibited the activation of Syk and Syk-dependent signaling proteins including LAT, PLCγ, Akt, and MAP kinases. Our results suggest that CYC116 could be used as an alternative therapeutic medication for mast cell-mediated allergic disorders, such as atopic dermatitis and allergic rhinitis.
Anaphylaxis ; Animals ; Cytokines ; Dermatitis, Atopic ; Hypersensitivity ; Interleukin-6 ; Mast Cells ; Mice ; Passive Cutaneous Anaphylaxis ; Phosphotransferases ; Rhinitis, Allergic

No abstract available.
Gastrointestinal Microbiome ; Stroke

This article has been retracted.

As the request of the authors, one paragraph has been changed.

Since scalp hair loss has increased recently even in young people, seriously affecting individual's quality of life, the hair growth-stimulating effects of Laminaria japonica extract (LJE) and Cistanche tubulosa extract (CTE) were investigated. After confirming anagen phase of follicles under shaving, male C57BL/6 mice were dermally applied with 3% Minoxidil or orally administered with the combinations of LJE and CTE for 21 days. Minoxidil promoted the hair regrowth and increased gamma-glutamyl transpeptidase (gamma-GTP) and alkaline phosphatase (ALP) activities. In addition, Minoxidil up-regulated epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) levels. Co-administration of LJE and CTE at 54 mg/kg LJE plus 162 mg/kg CTE exerted synergistic promoting effects on the hair regrowth, comparable to 3% Minoxidil. LJE preferentially enhanced ALP activity, while CTE increased both gamma-GTP and ALP activities as well as EGF and VEGF expressions. In vivo air pouch inflammation model, carrageenan-induced vascular exudation and increased nitric oxide and prostaglandin E2 concentrations in the exudates were synergistically suppressed by co-administration of LJE and CTE. In addition, inflammatory cell infiltration was substantially inhibited by the combinational treatment. The results suggest that combinational oral treatment with LJE and CTE in appropriate doses and ratios prevent hair loss and improve alopecia, which might be in part mediated by their anti-inflammatory activities.
Alkaline Phosphatase ; Alopecia ; Animals ; Cistanche* ; Dinoprostone ; Epidermal Growth Factor ; Exudates and Transudates ; gamma-Glutamyltransferase ; Hair* ; Humans ; Inflammation ; Laminaria* ; Male ; Mice ; Minoxidil ; Nitric Oxide ; Quality of Life ; Scalp ; Vascular Endothelial Growth Factor A

The effects of a beta-dunnione compound MB12662 on the gastric secretion and ulcers were investigated in rats. In order to assess the effects of MB12662 on the gastric secretion and acidity, rats were subjected to pylorus ligation operation, and 6 hours later, gastric fluid was collected. Treatment with MB12662 reduced the gastric fluid volume to 47.3% of control level and increased pH. In an alcohol-induced ulcer model, rats were orally administered 3 mL/kg of ethanol, and 1 hour later, the ulcer lesions ware measured under a stereomicroscope. MB12662 reduced ulcer index in a dose-dependent manner which was much stronger than a proton-pump inhibitor pantoprazole. In a stress-induced ulcer model, rats were subjected to water-immersion restraint stress, and 5 hours later, the ulcer lesions ware examined. MB12662 also attenuated the stress-induced gastric lesions, although the efficacy of MB12662 was lower than that of pantoprazole. Therefore, it is suggested that MB12662 could be a candidate compound for the prevention or treatment of gastric ulcers induced by gastric over-secretion and alcoholic hangover.
2-Pyridinylmethylsulfinylbenzimidazoles ; Alcoholics ; Animals ; Ethanol ; Humans ; Hydrogen-Ion Concentration ; Ligation ; Pylorus ; Rats ; Stomach Ulcer ; Ulcer

The neuroprotective effects of a butanol fraction of white rose petal extract (WRPE-BF) were investigated in a middle cerebral artery occlusion (MCAO) model. Seven week-old male rats were orally administered WRPE-BF for 2 weeks and subjected to MCAO for 2 h, followed by reperfusion. Twenty-four h later, MCAO-induced behavioral dysfunctions were markedly improved in a dose-dependent manner by pretreatment with WRPE-BF. Moreover, higher dose of WRPE-BF not only decreased infarction area but also effectively reduced astrogliosis. The expression of inducible nitric oxide synthase, cyclooxygenase-2, and glial fibrillary acidic protein in MCAO model were markedly inhibited by WRPE-BF treatment. Notably, WRPE-BF decreased nitric oxide and malondialdehyde levels in the striatum and subventricular zone of stroke-challenged brains. These data suggested that WRPE-BF may exert its neuroprotective effects via anti-oxidative and anti-inflammatory activities against ischemia-reperfusion brain injury and could be a good candidate as a therapeutic target for ischemic stroke.
Animals ; Brain ; Brain Injuries ; Cyclooxygenase 2 ; Glial Fibrillary Acidic Protein ; Humans ; Infarction ; Infarction, Middle Cerebral Artery* ; Male ; Malondialdehyde ; Middle Cerebral Artery* ; Neuroprotective Agents* ; Nitric Oxide ; Nitric Oxide Synthase Type II ; Rats ; Reperfusion ; Rosa* ; Stroke