The effect of rocuronium on ventilatory leak and sealing pressure using a supraglottic airway device: A randomized clinical trial.

BACKGROUND: The transition of ventilatory leak and sealing pressure in supraglottic airway devices after administration of neuromuscular blocking agents is unclear. We hypothesized that ventilatory leak would decrease due to the increase in sealing pressure after administration of 0.15 and 0.30 mg/kg rocuronium iv. METHODS: Forty patients were randomly assigned to a control group or one of two rocuronium groups. After induction of general anaesthesia, an i-gel® was inserted before rocuronium administration. The ventilatory leak and sealing pressure were measured immediately. Then, 0.15 mg/kg or 0.30 mg/kg rocuronium iv was administered and the ventilatory leak and sealing pressure were measured again. In the control group, measurements were obtained just after insertion of the supraglottic airway device and 5 minutes later, without any additional drug administration. RESULTS: Similar decrements in ventilatory leak of approximately 3% were registered in all three groups. There were no changes in sealing pressure in any of the groups. However, multiple logistic regression analysis demonstrated that the reduced height of the first twitch response to train-of-four stimulation after administration of rocuronium was a determinant of a decrease in sealing pressure (odds ratio: 0.97, 95% confidence interval: 0.95-0.99, P = .04). CONCLUSIONS: Our results suggest that ventilatory leak with a supraglottic airway device decreases independently of neuromuscular blockade, although the neuromuscular blockade may potentially decrease sealing pressure. Registration of Clinical trials: UMIN Clinical Trials Registry (registration ID: UMIN000027061, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000031018).

Response to rocuronium and its determinants in patients with myasthenia gravis: A case-control study.

BACKGROUND: Several previous studies using univariate analysis have suggested that the pre-anaesthetic train-of-four (TOF) ratio, concentration of anti-acetylcholine receptor (AChR) antibodies and the presence of preoperative generalised muscular involvement are determinants of an increased response to neuromuscular blocking agents (NMBAs) in patients with myasthenia gravis. However, the determinants of the response of patients with myasthenia gravis to rocuronium, which is expected to be used more frequently since the advent of sugammadex, have not been studied. OBJECTIVES: To clarify whether previously suggested determinants of the response to other intermediate-acting NMBAs would also affect the response to rocuronium and to reveal the determinants of the increased response to rocuronium in individual patients with myasthenia gravis using multivariate analysis. DESIGN: Case control study. SETTING: Kumamoto University Hospital, November 2010 to September 2013. PATIENTS: Thirty-eight patients with myasthenia gravis having surgery using a total intravenous anaesthetic technique were investigated. After induction of general anaesthesia, the 95% effective dose (ED95) of rocuronium was calculated using cumulative dose-finding methods. Neuromuscular function was monitored by acceleromyographic assessment of TOF responses of the adductor pollicis muscle to ulnar nerve stimulation. Patients were then divided into the increased response (ED95 <0.15 mg kg, n = 13) and non-increased response groups (ED95 ≥0.15 mg kg, n = 25). MAIN OUTCOME MEASURES: Demographic data, TOF ratio before rocuronium injection (baseline TOF ratio), concentration of anti-AChR antibodies, Osserman classification and treatment for myasthenia gravis in the two groups were compared. RESULTS: Stepwise logistic regression identified baseline TOF ratio and age of onset of myasthenia gravis as determinants of the increased response to rocuronium in patients with myasthenia gravis [odds ratios (95% confidence interval) of 0.87 (0.77 to 0.98; P = 0.02) and 0.92 (0.86 to 0.99; P = 0.03), respectively]. CONCLUSION: Multivariate analysis identified baseline TOF ratio and age of disease onset as determinants of the increased response to rocuronium in patients with myasthenia gravis. TRIAL REGISTRATION: Registered with UMIN Clinical Trials Registry, identifier: UMIN000006766.

In non-obese patients, duration of action of rocuronium is directly correlated with body mass index.

BACKGROUND: Administration of neuromuscular blocking agents using a dose calculated on actual body weight carries a risk of prolonged duration of action in obese patients whose body mass index (BMI) is > 30 kg · m(-2). In the present study, we hypothesized that there could be a correlation between BMI and the duration of action of rocuronium administered according to actual body weight in non-obese patients, in particular, overweight (BMI 25-30 kg · m(-2)) and underweight patients (BMI < 18.5 kg · m(-2)). METHODS: Sixteen female patients (BMI 15-30 kg · m(-2), aged 45-60 yr) scheduled for elective surgery under total intravenous anesthesia were included in this study. Rocuronium 0.9 mg · kg(-1) was administered, and adductor pollicis train-of-four responses following ulnar nerve stimulation were monitored every minute with acceleromyography. The times from the injection of rocuronium until spontaneous recovery of first twitch to 5% (5% Duration) and 25% (25% Duration) of baseline were measured, and the correlation with BMI was analyzed. RESULTS: A significant correlation between 5% Duration and BMI (r(2) = 0.56; P < 0.001) was found by linear regression analysis. A significant correlation was also found between 25% Duration and BMI (r(2) = 0.49; P = 0.003). CONCLUSION: In adult female patients with a BMI in the range of 15-30 kg · m(-2), the duration of action of rocuronium increases with BMI when the drug is administered on the basis of mg per actual kg body weight.

[The effect of rocuronium and sugammadex in hepatic tumor patients without preoperative hepatic impairment].

BACKGROUND: The effect of rocuronium and sugammadex in patients undergoing hepatectomy due to hepatic tumor without preoperative hepatic impairment were investigated. METHODS: We studied 15 patients undergoing hepatectomy and 20 patients undergoing non-hepatic surgery No patients had preoperative hepatic impairment. Anesthesia was induced and maintained with propofol and remifentanil. Train-of-four (TOF) responses of the adductor pollicis to the supramaximal ulnar nerve stimulation were monitored by acceleromyography. A single dose of rocuronium 0.9 mg x kg(-1) was administered, and after spontaneous recovery of T1 to 25%, rocuronium was infused continuously to keep the posttetanic count 1-2. After surgery, sugammadex 4 mg x kg(-1) was administered. RESULTS: In hepatectomy patients, duration from the administration of rocuronium to recovery of T1 to 25% was longer (88 +/- 20 vs 68 +/- 16 min, P < 0.01), and the total dose of rocuronium used during surgery was less (8.8 +/- 1.7 vs 11.4 +/- 2.7 microg x kg(-1) x min(-1), P < 0.01). However, there were no differences in the duration from administration of sugammadex to recovery of TOF ratio to 0.9 between two groups (138 +/- 55 vs 164 +/- 79 sec, P = 0.29). CONCLUSIONS: Rocuronium-induced neuromuscular block was prolonged in hepatectomy patients even without preoperative hepatic impairment but the reversal with sugammadex was effective.

[Transfusion-related acute lung injury caused by anti-leukocyte antibodies found in patient's serum and donor plasma].

We report a case of transfusion-related acute lung injury (TRALI) with anti-leukocyte antibodies detected both in the patient's serum and in the causative fresh frozen plasma. The patient was a 72-year-old Japanese woman who had undergone colectomy and stoma closure under general anesthesia. Intraoperatively she received 8 units of red cell concentrate and 12 units of fresh frozen plasma. At the end of surgery she was fully awake and extubated. Shortly after extubation her oxygen saturation dropped (90%) and she developed dyspnea. A chest X-ray revealed bilateral diffuse pulmonary edema without cardiac enlargement. The patient was re-intubated and placed on respiratory support with positive end-expiratory pressure ventilation. Her pulmonary edema improved and she was extubated again at 20 hours after surgery. Antibodies to human leukocyte antigen were detected in serum from the patient and in serum samples of the freshly frozen donor plasma; a crossmatch test of the patient's lymphocytes and donor serum was positive. We believe that anti-leukocyte antibodies caused TRALI via an immune-mediated mechanism.

Universal asymptotic correlation functions for point group C_{6v} and an observation for triangular lattice Q-state Potts model.

We investigate a universal curve in asymptotic correlation functions of off-critical systems that possess C_{6v} symmetry following the argument for C_{4v} symmetry in our previous paper [Phys. Rev. E 102, 032141 (2020)2470-004510.1103/PhysRevE.102.032141]. Unlike the C_{4v} case, a minimal asymptotic form exists, which contains only two free parameters: the normalization constant and the modulus of the universal curve. We perform large-scale Monte Carlo simulations of the triangular lattice Q-state Potts model above the transition temperature. For Q=1, 2, 3, and 4, we successfully obtain numerical evidence that the minimal form gives the leading asymptotic behavior. We also discuss the possibility that the corrections to the minimal form are expressed using this form as a building block. From the minimal form with optimized parameters, we derive the equilibrium crystal shape of the honeycomb lattice Potts model, which is given by an algebraic curve of genus 1 and is universal among models with C_{6v}. Although the curve differs from those obtained in the C_{4v} case, the latter curves also have genus 1. We indicate that the birational equivalence concept can play an important role in comparing asymptotic forms for different point group symmetries, for example, C_{6v} and C_{4v}.

Erratum: Asymptotic correlation functions in the Q-state Potts model: A universal form for point group C_{4v} [Phys. Rev. E 102, 032141 (2020)].

This corrects the article DOI: 10.1103/PhysRevE.102.032141.

The Occurrence of Early-Onset Neonatal Streptococcus pneumoniae Infection as a Result of Intrapartum Infection.

Early-onset neonatal infection caused by Streptococcus pneumoniae occurs rarely but has a high mortality rate. Due to the low detection rate of S. pneumoniae in maternal vaginal cultures, administering prophylactic antibiotics for S. pneumoniae to mothers before delivery is challenging. Herein, we present the case of a male newborn who was born at 38 weeks of gestation. The vaginal cultures of his mother before delivery did not reveal the presence of group B streptococcus (GBS) and S. pneumoniae. The newborn experienced respiratory distress six hours after birth and was diagnosed with congenital pneumonia. He was successfully treated with an artificial ventilator and antibiotics. The nasal cavity, external ear canal, and transtracheal tube sputum cultures of the neonate and the vaginal cultures of his mother were positive for S. pneumoniae serotype 3. This case indicates the occurrence of congenital S. pneumoniae infection as a result of intrapartum infection and highlights the necessity to consider S. pneumoniae as a causative agent of early-onset neonatal infection.

Fibroblast growth factor 2 induces apoptosis in the early primary culture of rat cortical neurons.

In the central nervous system, fibroblast growth factor 2 (FGF2) is known to have important functions in cell survival and differentiation. In addition to its roles as a neurotrophic factor, we found that FGF2 caused cell death in the early primary culture of cortical neurons. FGF2-induced neuronal cell death showed apoptotic characters, e.g., chromatin condensation and DNA fragmentation. The ultrastructural morphology of FGF2-treated neurons indicated apoptotic features such as progressive cell shrinkage, blebbing of the plasma membrane, loss of cytosolic organelles, clumping of chromatin, and fragmentation of DNA. Tyrosine kinase inhibitors significantly rescued neurons from FGF2-induced apoptosis. FGF2 potentiated a marked influx of Ca(2+) into neurons before apoptosis. Both a calcium chelator and L-type voltage-sensitive Ca(2+) channel (L-VSCC) blockers attenuated FGF2-induced apoptosis, whereas other blockers of VSCCs such as N-type and P/Q-types did not. Blockers of L-VSCCs significantly suppressed FGF2-enhanced Ca(2+) influx into neurons. Moreover, FGF2 also generated reactive oxygen species (ROS) before apoptosis. Radical scavengers reduced not only the FGF2-generated ROS, but also the FGF2-induced Ca(2+) influx and apoptosis. In conclusion, we demonstrated that FGF2 caused apoptosis via L-VSCCs in the early neuronal culture.

Neuferricin, a novel extracellular heme-binding protein, promotes neurogenesis.

We identified a novel extracellular heme-binding protein and named it neuferricin. The recombinant mouse neuferricin produced in High Five cells was secreted efficiently into the culture medium. Mouse neuferricin mRNA was expressed mainly in the brain at the embryo stage and gradually increased during development. At postnatal stage, it was widely expressed in the brain, heart, adrenal gland, and kidney. Mouse neuferricin has 263 amino acids. It has a cytochrome b5-like heme/steroid-binding domain and appeared to bind hemin because neuferricin solution, but not a solution of neuferricinDeltaHBD (a mutant lacking the heme-binding domain), was tinged with brown and had an absorbance peak at 402 nm. In addition, the experiment with anti-neuferricin antibody using heme-affinity chromatography proved that the endogenous neuferricin detected in the culture medium of Neuro2a cells was associated with hemin. Inhibition of endogenous neuferricin by RNA interference excessively promoted cell survival and proliferation and suppressed neurite outgrowth during the induction of differentiation in Neuro2a cells. Addition of recombinant mouse neuferricin, but not neuferricinDeltaHBD, suppressed survival of Neuro2a cells and rescued from the effects of neuferricin RNAi. In primary cultured mouse neural precursor cells, recombinant mouse neuferricin exhibited the ability to promote neurogenesis. The identification of neuferricin, a novel extracellular heme-binding protein with cytochrome b5-like heme/steroid-binding domain and its neurogenic activity, provide new insights not only into brain development but also the function of heme-binding proteins as extracellular signal transmitters.

Asymptotic correlation functions in the Q-state Potts model: A universal form for point group C_{4v}.

Reexamining algebraic curves found in the eight-vertex model, we propose an asymptotic form of the correlation functions for off-critical systems possessing rotational and mirror symmetries of the square lattice, i.e., the C_{4v} symmetry. In comparison with the use of the Ornstein-Zernike form, it is efficient to investigate the correlation length with its directional dependence (or anisotropy). We investigate the Q-state Potts model on the square lattice. Monte Carlo (MC) simulations are performed using the infinite-size algorithm by Evertz and von der Linden. Fitting the MC data with the asymptotic form above the critical temperature, we reproduce the exact solution of the the anisotropic correlation length (ACL) of the Ising model (Q=2) within a five-digit accuracy. For Q=3 and 4, we obtain numerical evidence that the asymptotic form is applicable to their correlation functions and the ACLs. Furthermore, we successfully apply it to the bond percolation problem which corresponds to the Q→1 limit. From the calculated ACLs, the equilibrium crystal shapes (ECSs) are derived via duality and Wulff's construction. Regarding Q as a continuous variable, we find that the ECS of the Q-state Potts model is essentially the same as those of the Ising models on the Union Jack and 4-8 lattices, which are represented in terms of a simple algebraic curve of genus 1.

Neudesin, an extracellular heme-binding protein, suppresses adipogenesis in 3T3-L1 cells via the MAPK cascade.

Adult mice abundantly express neudesin, an extracellular heme-binding protein with neurotrophic activity, in white adipose tissues. At the early stage of adipocyte differentiation during adipogenesis, however, the expression of neudesin decreased transiently. Neudesin-hemin significantly suppressed adipogenesis in 3T3-L1 cells. The knockdown of neudesin by RNA interference markedly promoted adipogenesis in 3T3-L1 cells and decreased MAPK activation during adipocyte differentiation. The addition or knockdown of neudesin affected the expression of C/EBPalpha and PPARgamma but not of C/EBPbeta. These findings suggest that neudesin plays a critical role in the early stage of adipocyte differentiation in which C/EBPbeta induces PPARgamma and C/EBPalpha expressions, by controlling the MAPK pathway.

[An elderly case of recurrent colon cancer responding to weekly S-1 chemotherapy leading to partial response].

An 82-year-old female with unresectable colon cancer accompanied by multiple lung metastasis was treated with S-1. Our course consisted of S-1(80 mg/body)from day 1 to 5 followed by 2 days rest. After 14 courses, multiple lung metastasis decreased in size. After 20 courses, the multiple lung metastasis disappeared and local recurrence of colon cancer decreased. Weekly S-1 leads to a partial response. Our chemotherapy showed simple and good compliance for a patient over 80 years old.

Effects of an endothelin B receptor agonist on secretory phospholipase A2-IIA-induced apoptosis in cortical neurons.

Endothelin (ET), a vasoconstrictive peptide, acts as an anti-apoptotic factor, and endothelin receptor B (ETB receptor) is associated with neuronal survival in the brain. Human group IIA secretory phospholipase A2 (sPLA2-IIA) is expressed in the cerebral cortex after brain ischemia and causes neuronal cell death via apoptosis. In primary cultures of rat cortical neurons, we investigated the effects of an ETB receptor agonist, ET-3, on sPLA2-IIA-induced cell death. sPLA2-IIA caused neuronal cell death in a concentration- and time-dependent manner. ET-3 significantly prevented neurons from undergoing sPLA2-IIA-induced cell death. These agonists reversed sPLA2-IIA-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Before cell death, sPLA2-IIA potentiated the influx of Ca2+ into neurons. Blockers of the L-type voltage-dependent calcium channel (L-VSCC) not only suppressed the Ca2+ influx, but also exhibited neuroprotective effects. As well as L-VSCC blockers, ET-3 significantly prevented neurons from sPLA2-IIA-induced Ca2+ influx. An ETB receptor antagonist, BQ788, inhibited the effects of ET-3. The present cortical cultures contained few non-neuronal cells, indicating that the ETB receptor agonist affected the survival of neurons directly, but not indirectly via non-neuronal cells. In conclusion, we demonstrate that the ETB receptor agonist rescues cortical neurons from sPLA2-IIA-induced apoptosis. Furthermore, the present study suggests that the inhibition of L-VSCC contributes to the neuroprotective effects of the ETB receptor agonist.

Structure-activity relationships of a novel class of endothelin-A receptor antagonists and discovery of potent and selective receptor antagonist, 2-(benzo[1,3]dioxol-5-yl)-6-isopropyloxy-4-(4-methoxyphenyl)-2H-chromene-3-carboxylic acid (S-1255). 1. Study on structure-activity relationships and basic structure crucial for ET(A) antagonism.

A novel series of endothelin-A (ET(A)) selective receptor antagonists having a 2H-chromene skeleton are described. A lead compound, 2-(benzo[1,3]dioxol-5-yl)-2H-chromene-3-carboxylic acid (3), was found by modifications of our own angiotensin II antagonist. A structure-activity relationship (SAR) study of 3 reveals that the structural requirements essential for potent and selective ET(A) receptor binding affinity are the m,p-methylenedioxyphenyl, carboxyl, and isopropoxy groups at the 2-, 3-, and 6-positions, respectively, on the (R)-2H-chromene skeleton. The substituent at the 4-position is also important for improving the activity, and various hydrophobic functional groups of 6-9 A such as liner, branched, and cyclic aliphatic groups, unsubstituted and substituted aryl groups, and even halogen atoms were acceptable. These results suggest that (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acid, formula 108, is the crucial basic structure to be recognized by the ET(A) receptor. The most potent compound is (R)-48 (S-1255), which binds to the ET(A) receptor with an IC(50) value of 0.19 nM and is 630-fold selective for the ET(A) receptor than for the ET(B) receptor. This compound has 55% oral bioavailability in rats. On the basis of the SAR, the roles of each substituent in the receptor binding are discussed.

Protective effects of a selective L-type voltage-sensitive calcium channel blocker, S-312-d, on neuronal cell death.

Amyloid beta protein (Abeta)- and human group IIA secretory phospholipase A(2) (sPLA(2)-IIA)-induced neuronal cell death have been established as in vitro models for Alzheimer's disease (AD) and stroke. Both sPLA(2)-IIA and Abeta causes neuronal apoptosis by increasing the influx of Ca(2+) through L-type voltage-sensitive Ca(2+) channel (L-VSCC). In the present study, we evaluated effects of a selective L-VSCC blocker, S-(+)-methyl 4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitro-phenyl)thieno[2,3-b]pyridine-5-carboxylate (S-312-d), on Abeta- and sPLA(2)-IIA-induced neuronal apoptosis in primary cultures of rat cortical neurons. S-312-d significantly rescued cortical neurons from Abeta- and sPLA(2)-IIA-induced cell death. Both cell death stimuli caused the appearance of apoptotic features such as plasma membrane blebs, chromatin condensation, and DNA fragmentation. S-312-d completely suppressed these apoptotic features. Before apoptosis, the two death ligands markedly enhanced an influx of Ca(2+) into neurons. S-312-d significantly prevented neurons from sPLA(2)-IIA- and Abeta-induced Ca(2+) influx. Furthermore, the neuroprotective effect of S-312-d was more potent than that of another L-VSCC blocker, nimodipine. On the other hand, blockers of other VSCCs such as the N-type and P/Q-type calcium channels had no effect on the neuronal cell death, apoptotic features and Ca(2+) influx. In conclusion, we demonstrated that S-312-d rescues cortical neurons from Abeta- and sPLA(2)-IIA-induced apoptosis.

Effects of endothelin B receptor agonists on amyloid beta protein (25-35)-induced neuronal cell death.

Endothelin (ET), a vasoconstrictive peptide, acts as an anti-apoptotic factor, and endothelin receptor B (ET(B) receptor) is associated with neuronal survival in the brain. In the Alzheimer's disease (AD) brain, accumulation of amyloid beta protein (Abeta) is thought to cause neuronal cell death via apoptosis. In the present study, we investigated effects of ET(B) receptor agonists on Abeta-induced neuronal cell death. In primary cultures of rat cortical neurons, Abeta(25-35) caused neuronal cell death in a concentration- and time-dependent manner. Abeta(25-35)-induced neuronal cell death was accompanied by chromatin condensation and DNA fragmentation, exhibiting apoptotic features. ET-3 and IRL-1620, ET(B) receptor agonists, significantly prevented neurons from undergoing Abeta(25-35)-induced cell death. Prior to cell death, Abeta increased concentration of intracellular Ca(2+) ([Ca(2+)](i)). Nimodipine, an L-type voltage-sensitive Ca(2+) channel (L-VSCC) blocker, suppressed the Abeta-induced Ca(2) influx, and attenuated Abeta-induced neuronal apoptosis. On the other hand, omega-conotoxin GIVA, an N-type VSCC blocker and omega-conotoxin MVIIC and omega-agatoxin IVA, P/Q-type VSCC blockers, had no effect. ET-3 and IRL-1620 significantly blocked Abeta(25-35)-induced Ca(2) influx. Furthermore, BQ788, an ET(B) receptor antagonist, inhibited both an anti-apoptotic effect and an L-VSCC-inactivating effect of ET(B) receptor agonists. In conclusion, ET(B) receptor agonists exhibit a protective effect against neurotoxicity of Abeta. Furthermore, these agonists appear to act as anti-apoptotic factors by blocking of L-VSCCs.

Effect of Gas6 on secretory phospholipase A(2)-IIA-induced apoptosis in cortical neurons.

Gas6, a product of the growth-arrest-specific gene 6, protects cortical neurons from amyloid beta protein (Abeta)-induced apoptosis. Neuronal apoptosis is also caused by human group IIA secretory phospholipase A(2) (sPLA(2)-IIA), which is expressed in the cerebral cortex after brain ischemia. sPLA(2)-IIA induces Ca(2+) influx via L-type voltage-sensitive calcium channels (L-VSCCs), leading to its neurotoxicity. In the present study, we investigated effects of Gas6 on sPLA(2)-IIA-induced cell death in primary cultures of rat cortical neurons. sPLA(2)-IIA caused neuronal cell death in a concentration- and time-dependent manner. Gas6 significantly prevented neurons from sPLA(2)-IIA-induced cell death. Gas6 suppressed sPLA(2)-IIA-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Prior to cell death, sPLA(2)-IIA increased the influx of Ca(2+) into neurons through L-VSCCs. Gas6 significantly inhibited the sPLA(2)-IIA-induced Ca(2+) influx. The blocker of L-VSCCs also suppressed sPLA(2)-IIA-induced neuronal cell death. The cortical cultures contained few non-neuronal cells, indicating that Gas6 affected the survival of neurons directly, but not indirectly via non-neuronal cells. In conclusion, we demonstrate that Gas6 rescues cortical neurons from sPLA(2)-IIA-induced apoptosis. Furthermore, the present study indicates that inhibition of L-VSCC contributes to the neuroprotective effect of Gas6.

Functions of MAPR (membrane-associated progesterone receptor) family members as heme/steroid-binding proteins.

Progesterone receptor membrane component 1 (PGRMC1), PGRMC2, neudesin, and neuferricin all contain a cytochrome b5-like heme/steroid-binding domain and belong to the membrane-associated progesterone receptor (MAPR) family. Their amino acid sequences are well conserved among vertebrates, from humans to zebrafish. MAPR family genes are abundantly expressed in the central nervous system and exhibit neurotrophic effects in neural cells. During lipid metabolism, PGRMC1 regulates cholesterol synthesis, and neudesin plays a role in adipogenesis. Their bioactivities are dependent on the binding of heme to their cytochrome b5-like heme/steroid-binding domains. Conversely, it has been reported that the binding of steroids to MAPR family proteins induces biological responses that are unrelated to the nuclear steroid receptors. The interaction between PGRMC1 and progesterone promotes cell survival and damage resistance by progesterone. Moreover, MAPR family proteins exhibit a unique expression pattern in breast cancer, indicating the possibility of using MAPR family members as drug target in breast cancer. In this review, we summarize the identification, structure, and bioactivity of members of the MAPR family, and present an essential overview of the current understanding of their physiological roles.

Proteomic identification of protein targets for 15-deoxy-Δ(12,14)-prostaglandin J2 in neuronal plasma membrane.

15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) is one of factors contributed to the neurotoxicity of amyloid ß (Aß), a causative protein of Alzheimer's disease. Type 2 receptor for prostaglandin D(2) (DP2) and peroxysome-proliferator activated receptorγ (PPARγ) are identified as the membrane receptor and the nuclear receptor for 15d-PGJ(2), respectively. Previously, we reported that the cytotoxicity of 15d-PGJ(2) was independent of DP2 and PPARγ, and suggested that 15d-PGJ(2) induced apoptosis through the novel specific binding sites of 15d-PGJ(2) different from DP2 and PPARγ. To relate the cytotoxicity of 15d-PGJ(2) to amyloidoses, we performed binding assay [(3)H]15d-PGJ(2) and specified targets for 15d-PGJ(2) associated with cytotoxicity. In the various cell lines, there was a close correlation between the susceptibilities to 15d-PGJ(2) and fibrillar Aß. Specific binding sites of [(3)H]15d-PGJ(2) were detected in rat cortical neurons and human bronchial smooth muscle cells. When the binding assay was performed in subcellular fractions of neurons, the specific binding sites of [(3)H]15d-PGJ(2) were detected in plasma membrane, nuclear and cytosol, but not in microsome. A proteomic approach was used to identify protein targets for 15d-PGJ(2) in the plasma membrane. By using biotinylated 15d-PGJ(2), eleven proteins were identified as biotin-positive spots and classified into three different functional proteins: glycolytic enzymes (Enolase2, pyruvate kinase M1 (PKM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH)), molecular chaperones (heat shock protein 8 and T-complex protein 1 subunit α), cytoskeletal proteins (Actin ß, F-actin-capping protein, Tubulin ß and Internexin α). GAPDH, PKM1 and Tubulin ß are Aß-interacting proteins. Thus, the present study suggested that 15d-PGJ(2) plays an important role in amyloidoses not only in the central nervous system but also in the peripheral tissues.