Characteristics and risk factors of interstitial lung disease induced by chemotherapy for lung cancer

Drug-induced interstitial lung disease (DILD) is generally a serious adverse effect and almost always necessitates the discontinuation of the offending drug. Cancer pharmacotherapy is strongly associated with DILD, and the risk of DILD has been suggested to be higher in patients with lung cancer because of preexisting pneumonic disease. The aim of this retrospective study was to identify the risk factors and prognostic factors for early death from interstitial lung disease (ILD) induced by chemotherapy for lung cancer. The medical records of 459 patients who underwent chemotherapy for lung cancer between April 2007 and March 2013 were analyzed with regard to patient background and DILD development, initial symptoms, and prognosis. A total of 33 patients (7.2%) developed chemotherapy-induced ILD. The most frequently observed initial symptom was dyspnea (94.3%). Preexisting ILD was identified as a risk factor for DILD (odds ratio [OR] = 5.38; 95% CI = 2.47-11.73; P < 0.01). Among the 33 patients who developed DILD, 10 patients suffered an early death despite steroid therapy. Poor prognostic factors included epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) use (OR = 9.26; 95% CI = 1.05-82.0; P < 0.05) and 2 or more prior chemotherapy regimens (OR = 6.95; 95% CI = 1.14-42.3; P < 0.05). Many lung cancer patients have coexisting ILD, and these patients have a high risk of developing chemotherapy-induced ILD. In addition, patients with DILD who underwent EGFR-TKI therapy and 2 or more prior chemotherapy regimens had a higher risk of fatal outcome.


Spontaneously hyperactive MEK-Erk pathway mediates paradoxical facilitation of cell proliferation in mild hypoxia

Oxygen is important for common eukaryotic cells to generate ATP. Pathophysiological conditions such as ischemic diseases cause tissue hypoxia. In addition, oxygen availability in deep tissues is supposed to be far lower than surrounding atmosphere even in healthy animals, and the oxygen partial pressures in most normal tissues are estimated to be around 40-50mmHg, so-called mild hypoxia. Recent studies have demonstrated that mild hypoxia has distinct effects on living cells from severe hypoxia. For instance, mild hypoxia was reported to promote cell reprogramming. Although severe hypoxia is known to inhibit cell proliferation, mild hypoxia has been paradoxically demonstrated to increase cell proliferation. However, it has not been clarified by which molecular mechanisms mild hypoxia evokes the discontinuous increment of cell proliferation. We established experimental conditions showing the opposite influences of mild and severe hypoxia on cell proliferation using undifferentiated Caco2 human colon carcinoma cells in order to clarify the underlying molecular mechanism. The basal activity of Erk, which is a typical mediator of mitogenic signals, is spontaneously increased specifically in cells exposed to mild hypoxia, and inhibition of MEK, an upstream kinase of the Erk, completely inhibited the mild hypoxia-induced enhancement of cell proliferation. Spontaneous hyperactivation of the MEK-Erk pathway by mild hypoxia should be the plausible molecular mechanism of the paradoxical promotion of cell proliferation. Our findings will provide clues to the molecular basis of mild hypoxia-evoked phenomena such as cell reprogramming.

Biochimica et Biophysica Acta (BBA) - General Subjects


Effect of ghrelin on autonomic activity in healthy volunteers.

Ghrelin is a novel growth hormone (GH)-releasing peptide originally isolated from the stomach. Recently, we have shown that ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction. In the present study, we evaluated the effect of ghrelin on autonomic nerve activity in healthy human subjects. An intravenous bolus of human synthetic ghrelin (10g/kg) was administered to 10 healthy men (mean age, 33 years). Holter monitoring assessment was performed before and during 2h after the ghrelin therapy. The standard deviation of normal RR intervals (SDNN), square root of the mean of the sum of the squares of differences between adjacent RR intervals (rMSSD), high-frequency power (HF), and low-frequency power (LF) were analyzed. Blood samples were also obtained before and after the therapy. A single administration of ghrelin decreased both heart rate and blood pressure. Interestingly, ghrelin significantly decreased the LF and LF/HF ratio of heart rate variability and increased the SDNN, rMSSD, and HF. Ghrelin also elicited a marked increase in circulating GH, but not insulin-like growth factor-1. These data suggest that ghrelin might suppress cardiac sympathetic nerve activity and stimulate cardiac parasympathetic nerve activity.


Investigation of the Cleanliness of Hospital Environmental Surfaces by Adenosine Triphosphate Bioluminescence Assay

This study evaluated the combined use of adenosine triphosphate (ATP) bioluminescence and microbiological assays for monitoring environmental surfaces in a teaching hospital to develop a method for rapid detection of microbial contamination that could constitute a health risk to patients. ATP bioluminescence assay and microbiological screening were performed of various surfaces of toilet facilities in outpatient wards. In each of the five sites screened, the ATP levels were significantly higher than on a cleaned, disinfected stainless steel surface, indicating that all screened surfaces were "high-touch" surfaces and the surfaces harbored significantly higher levels of certain organic matter. The microbiological assay confirmed that the microbiological contamination had spread throughout the screened sites. The ATP values of the samples positive for microbes occurred in a significantly higher range than those of the samples negative for microbes (p<0.01). However, no linear relationship was established between the ATP values and aerobic colony counts of the screened sites. These results clearly imply that the use of ATP bioluminescence to measure the microbial contamination of an environment yields qualitative rather than quantitative data. In conclusion, ATP monitoring is a rapid and convenient method to assess environmental contamination and persistence of microbes and to monitor the effectiveness of current cleaning practices.

病院環境表面のモニタリングについて，アデノシン三リン酸(ATP)生物発光および微生物学検定を組み合わせて使用することにより評価した．目的は，患者に対して危険をもたらしうる微生物汚染の迅速な検知方法を開発することである．この目的のために，私たちは，外来患者病棟におけるトイレ設備表面のATP生物発光分析および微生物学的検査を行なった．5か所のスクリーニング部位はすべて，清潔で消毒されたステンレス鋼表面よりも著しく高いATPレベルを示し，高度接触表面であること，そして有意に高い濃度の有機物を保持していることがわかった．微生物学的検定により，微生物汚染がスクリーニング部位の至る所に広がっていることを確認した．微生物が検出されるサンプルのATP値は，微生物が検出されないサンプルのATP値より有意に高い範囲にシフトしていた(p<0.01)．しかしながら，スクリーニング部位のATP値と好気性コロニー数との間の直線的関係は確立されなかった．これらの結果は，環境の微生物汚染の測定においてATP生物発光を使用して得られるデータは，定量的ではなく定性的なものであることを明白に示唆している．結論として，ATPモニタリングは，微生物による環境汚染およびそれが持続的な汚染状態にある可能性を把握し，院内環境に対する現在の清掃方法に警鐘を鳴らすうえで，迅速かつ簡便な優れた方法である．

Japanese Journal of Infection Prevention and Control


Risk Factors for Early-Onset Peripheral Neuropathy Caused by Vincristine in Patients With a First Administration of R-CHOP or R-CHOP-Like Chemotherapy

Peripheral neuropathy is a well-known side effect of vincristine (VCR), a microtubule inhibitor used for R-CHOP or R-CHOP-like (namely R-CVP and R-THP-COP) regimens. Previous studies have shown that both the total dose of VCR and the number of treatment cycles are related to the incidence of VCR-induced peripheral neuropathy (VIPN). However, VIPN will also occur during the first treatment cycle regardless of the total dose of VCR or number of treatment cycles (early-onset VIPN). There is little information about early-onset VIPN, and it is difficult to predict. The present study's goal was to identify risk factors for early-onset VIPN. We analyzed the case records of patients who had their first administration of an R-CHOP or R-CHOP-like regimen between April 2008 and August 2013 at Tokushima University Hospital in Tokushima, Japan. To identify the risk factors for early-onset VIPN, we performed univariate and multivariate logistic regression analyses. Forty-one patients underwent an R-CHOP or R-CHOP-like regimen for the first time at Tokushima University Hospital between April 2008 and August 2013, and 14 patients had grade 1 or higher early-onset VIPN. A univariate analysis revealed that age, the dose of VCR and the concomitant use of aprepitant appeared to be the risk factors of early-onset VIPN. In our calculation using receiver-operator characteristics curves, the cut-off value for patient age was 65 years and that of the dose of VCR was 1.9 mg. A multivariate analysis revealed that VCR dose ≥ 1.9 mg and the concomitant use of the antiemetic aprepitant were independent risk factors for early-onset VIPN. Our present study showed that the patients who had VCR dose ≥ 1.9 mg and the concomitant use of aprepitant had the risk for early-onset VIPN. This suggests that it is important to use aprepitant in light of the risk of early-onset VIPN and the benefit of aprepitant's antiemetic effect in R-CHOP and R-CHOP-like regimens.


Serious adverse events and compensation in registration trials: a review of data from a Japanese university hospital.

Clinical trials leading to regulatory approval, or registration trials, play a central role in the development of drugs and medical devices. The contribution of support staff, such as the clinical research coordinator (CRC) and administrative officers, in registration trials is now widely recognized. Attending to serious adverse events is an important duty of the CRC and investigators alike, and managing these complications and compensation constitutes a key responsibility. We retrospectively examined the frequency of serious adverse events and compensation events reported from 2007 through 2011 at Tokushima University Hospital, an academic hospital in rural Japan. We present herein the results of our analysis. Over the five-year period, 284 subjects participating in 106 registration trials experienced a total of 43 serious adverse events, and eight compensation events were documented. Among the serious adverse events, 35 (81.4%) were considered not related to the investigational drug, and 17 (39.5%) resulted in withdrawal of the study drug. Patients with malignant diseases experienced serious adverse events significantly more frequently compared to those with non-malignant diseases (28.3% versus 8.2%, respectively; P < 0.01). The CRC should be vigilant for serious adverse events in oncology clinical trials due to the generally higher frequency of these complications in subjects with malignancy. However, on an individual basis, the CRC may be seldom involved in the process for compensating serious adverse events. Therefore, the CRC's ability to share such experiences may serve as an opportunity for educating clinical trial support staff at the study site as well as those at other sites. However, further study is warranted to determine the role of the clinical trial support staff in optimizing methods for managing adverse events requiring compensation in registration trials.


Direct Determination of ABO Blood Group Genotypes from Whole Blood Using PCR-Amplification of Specific Alleles Method


Identification of the Risk Factors Associated with Hypocalcemia Induced by Denosumab

Denosumab, a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor-κB ligand, inhibits the activation of osteoclasts. Some clinical trials have shown that denosumab suppresses bone resorption in patients with advanced cancer, but hypocalcemia has been reported as a serious adverse effect after the administration of denosumab. It is difficult to predict hypocalcemia in such cases because the risk factors for denosumab-induced hypocalcemia have not been reported. Accordingly, the aim of the present study was to identify the risk factors for hypocalcemia induced by denosumab. We retrospectively reviewed the records of patients who had received denosumab at Tokushima University Hospital between April 2012 and May 2013. Fifty-three patients were analyzed and eleven patients had hypocalcemia after administration of denosumab. Univariate logistic regression analysis revealed that the patients who had not been administered zoledronic acid before receiving denosumab or had lower creatinine clearance (CCr) appeared to have a higher risk of hypocalcemia (p<0.05). The cut off value of CCr was 50.4 ml/min calculated by receiver-operator characteristics curves. Moreover, multivariate logistic regression analysis revealed that non-administration of zoledronic acid (odds ratio 10.43, p<0.05) and CCr less than 50.0 ml/min (odds ratio 5.90, p<0.05) were independent risk factors for denosumab-induced hypocalcemia. These findings provide useful information regarding the monitoring of hypocalcemia in patients receiving denosumab.


A novel targeting therapy of malignant mesothelioma using anti-podoplanin antibody

Podoplanin (Aggrus), which is a type I transmembrane sialomucin-like glycoprotein, is highly expressed in malignant pleural mesothelioma (MPM). We previously reported the generation of a rat anti-human podoplanin Ab, NZ-1, which inhibited podoplanin-induced platelet aggregation and hematogenous metastasis. In this study, we examined the antitumor effector functions of NZ-1 and NZ-8, a novel rat-human chimeric Ab generated from NZ-1 including Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against MPM in vitro and in vivo. Immunostaining with NZ-1 showed the expression of podoplanin in 73% (11 out of 15) of MPM cell lines and 92% (33 out of 36) of malignant mesothelioma tissues. NZ-1 could induce potent ADCC against podoplanin-positive MPM cells mediated by rat NK (CD161a(+)) cells, but not murine splenocytes or human mononuclear cells. Treatment with NZ-1 significantly reduced the growth of s.c. established tumors of MPM cells (ACC-MESO-4 or podoplanin-transfected MSTO-211H) in SCID mice, only when NZ-1 was administered with rat NK cells. In in vivo imaging, NZ-1 efficiently accumulated to xenograft of MPM, and its accumulation continued for 3 wk after systemic administration. Furthermore, NZ-8 preferentially recognized podoplanin expressing in MPM, but not in normal tissues. NZ-8 could induce higher ADCC mediated by human NK cells and complement-dependent cytotoxicity as compared with NZ-1. Treatment with NZ-8 and human NK cells significantly inhibited the growth of MPM cells in vivo. These results strongly suggest that targeting therapy to podoplanin with therapeutic Abs (i.e., NZ-8) derived from NZ-1 might be useful as a novel immunotherapy against MPM.


Nitrosonifedipine ameliorates angiotensin II-induced vascular remodeling via antioxidative effects

Nifedipine is unstable under light and decomposes to a stable nitroso analog, nitrosonifedipine (NO-NIF). The ability of NO-NIF to block calcium channels is quite weak compared with that of nifedipine. Recently, we have demonstrated that NO-NIF reacts with unsaturated fatty acid leading to generate NO-NIF radical, which acquires radical scavenging activity. However, the effects of NO-NIF on the pathogenesis related with oxidative stress, such as atherosclerosis and hypertension, are unclear. In this study, we investigated the effects of NO-NIF on angiotensin II (Ang II)-induced vascular remodeling. Ang II-induced thickening and fibrosis of aorta were inhibited by NO-NIF in mice. NO-NIF decreased reactive oxygen species (ROS) in the aorta and urinary 8-hydroxy-20-deoxyguanosine. Ang II-stimulated mRNA expressions of p22(phox), CD68, F4/80, monocyte chemoattractant protein-1, and collagen I in the aorta were inhibited by NO-NIF. Moreover, NO-NIF inhibited Ang II-induced cell migration and proliferation of vascular smooth muscle cells (VSMCs). NO-NIF reduced Ang II-induced ROS to the control level detected by dihydroethidium staining and lucigenin chemiluminescence assay in VSMCs. NO-NIF suppressed phosphorylations of Akt and epidermal growth factor receptor induced by Ang II. However, NO-NIF had no effects on intracellular Ca(2+) increase and protein kinase C-δ phosphorylation induced by Ang II in VSMCs. The electron paramagnetic resonance spectra indicated the continuous generation of NO-NIF radical of reaction with cultured VSMCs. These findings suggest that NO-NIF improves Ang II-induced vascular remodeling via the attenuation of oxidative stress.

Naunyn-Schmiedeberg's Archives of Pharmacology


Plasma dipeptidyl peptidase 4 activity correlates with body mass index and the plasma adiponectin concentration in healthy young people

We previously found that plasma dipeptidyl peptidase 4 (DPP4) activity was associated with the development of obesity, type 2 diabetes, and type 1 diabetes using animal models. In this study, we investigated whether DPP4 activity is correlated with the clinical parameters of obesity and/or diabetes in healthy young subjects. Body mass index (BMI), plasma DPP4 activity, total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, fasting blood glucose, adiponectin concentration, and body fat were measured in 165 subjects (110 males and 55 females, age 23.2 ± 2.4 years). In correlation analyses, DPP4 activity displayed strong positive correlations with BMI (p = 5.5 × 10(-5)) and total cholesterol (p = 0.0014), and a negative correlation with the plasma adiponectin concentration (p = 0.013), but not fasting blood glucose. Our findings suggest that plasma DPP4 activity is correlated with the clinical parameters of obesity rather than diabetes in young people.


Effects of mechanical pressure on cytoskeleton in human umbilical vein endothelial cells cultured in a newly developed chamber.

新規開発培養チャンバーを用いた物理的圧迫によるHUVEC細胞骨格への影響


Multiple effects of statins in patients with bacterial infectious diseases

細菌感染症患者におけるスタチンの多面的効果

Statins, treatments for dyslipidemia, have been reported to possess effects leading to therepair of the vascular endothelium, as well as anti-oxidative and anti-inflammatory effects, and theirclinical usefulness has been focused on. It was also reported in previous clinical research thatbacteremia patients on statins showed a lower mortality compared to those not receiving statins,and atherosclerosis patients on statins showed a significantly lower rate of severe or fatal sepsiscompared to those not receiving them. We conducted a case-control study involving patientshospitalized in Tokushima University Hospital to evaluate the relationship between taking/nottaking statins and bacterial infectious diseases. As a result, there was no relationship betweentaking/not taking statins and the overall patients with bacterial infectious diseases, but sepsispatients on statins showed a significantly lower mortality. The taking of statins was suggested tobe useful for patients with bacterial infectious diseases, particularly males.


Anti-obesity effects of Schisandra chinensis fruit water extract in rats fed a high-fat diet

Obesity has become a major public health problem worldwide. To date, many studies on obesity prevention have been performed. In this study, we examined the anti-obesity effects of <I>Schisandra chinensis</I> (Turcz.) Baill. fruit (SC) water extract in rats fed a high-fat diet. We gave the rats high-fat chow including SC water extract for 10 weeks. Although these rats ate the same amount of chow as the high-fat diet group, their weight gain was significantly inhibited compared to that in the high-fat diet group. Moreover, the SC group showed significantly decreased epididymal fat weight and levels of plasma triglycerides, total cholesterol, and leptin compared to the high-fat diet group. In the oral glucose tolerance test (OGTT), the SC group showed lower blood glucose levels than the high-fat diet group 90 min after eating. This is the first study to show that SC water extract has anti-obesity effects. It may be beneficial to drink SC water extract or tea after eating to prevent obesity.

肥満は社会的問題となっており， 予防対策に関する研究が進められている． 本研究では， 五味子 (チョウセンゴミシ果実) の肥満予防に対する有効性について検討した． 五味子水抽出エキスを高脂肪食に混合してラットに投与し， 肥満に関わるパラメーターに対する影響を検討した． 10週間自由摂食させた結果， 摂食量は変わらないにもかかわらず五味子水抽出エキス混合食投与群では高脂肪食のみ投与されていた群より有意な体重減少， 内臓脂肪量の減少， 血漿中のトリグリセリド減少が見られた． さらに， 五味子水抽出液混合食を投与した群では， 高脂肪食のみ投与した群と比較して脂肪組織は普通食摂食群と同程度に小さく， ブドウ糖負荷試験において90分後の血糖値は高脂肪食投与群より有意に低かった． 以上のことより五味子水抽出エキスは肥満の予防に有効である可能性が示唆された．


Changes in DNA structure in the DPI-induced apoptosis in cultured human HepG2 cells

DPIにより誘導されるヒト培養HepG2細胞死のDNA構造の解明


Simvastatin represses translocation of Pseudomonas aeruginosa across Madin-Darby canine kidney cell monolayers

Pseudomonas aeruginosa causes both invasive (bacteremic) and chronic noninvasive infections. An increase in intestinal epithelial permeability is a characteristic of severe sepsis. Alterations in the normal barrier function of the gut mucosa may result in the translocation of microbial cells and products. On the otherhand, it has been demonstrated that statin use is associated with a lower risk of mortality from bloodstream infections. Therefore, we investigated the ability of P. aeruginosa PAO1 to translocate across the Madin-Darby canine kidney (MDCK) cell monolayers in the presence and absence of simvastatin. The bacteria readily translocated across MDCK cell monolayers after 3 h of infection irrespective of the presence or absence of the drug in the medium. However, the bacteria were less able to penetrate the MDCK monolayers in the presence of simvastatin than in its absence. A gentamicin survival assay demonstrated that simvastatin did not affect the bacteria's invasive behavior in the MDCK cells.

The Journal of Medical Investigation : JMI


Iron reduction by deferoxamine leads to amelioration of adiposity via the regulation of oxidative stress and inflammation in obese and type 2 diabetes KKAy mice.

Iron is an essential trace metal for most organisms. However, excess iron causes oxidative stress through production of highly toxic hydroxyl radicals via the Fenton/Haber-Weiss reaction. Iron storage in the body is reported to be associated with fat accumulation and type 2 diabetes mellitus. We investigated the role of iron in adiposity by using KKAy mice and obese and diabetic model mice. Eight-week-old KKAy mice were divided into two groups and treated with deferoxamine (DFO), an iron chelator agent, or a vehicle for 2 wk. DFO treatment diminished fat iron concentration and serum ferritin levels in KKAy mice. Fat weight and adipocyte size were reduced significantly in DFO-treated mice compared with vehicle-treated mice. Macrophage infiltration into fat was also decreased in DFO-treated mice compared with vehicle-treated mice. Superoxide production and NADPH oxidase activity in fat, as well as urinary 8-hydroxy-2'-deoxyguanosine excretion, were decreased in KKAy mice after DFO treatment while p22(phox) expression in adipose tissue was diminished in such mice. Ferritin expression in the fat of DFO-treated KKAy mice was decreased. In addition, F4/80-positive cells also presented through both p22(phox) and ferritin expression. The mRNA expression levels of inflammatory cytokines were also reduced in fat tissue of DFO-treated mice. These findings suggest that reduction of iron levels ameliorates adipocyte hypertrophy via suppression of oxidative stress, inflammatory cytokines, and macrophage infiltration, thereby breaking a vicious cycle in obesity.

American Journal of Physiology, Endocrinology and Metabolism


Hypertension as a predictive factor of effect of bevacizumab in treatment of colorectal cancer

Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) for treatment of metastatic colorectal cancer. Recently, much evidence has suggested that bevacizumab-induced hypertension might be predictive of the effect of bevacizumab. The aim of our study is to retrospectively assess the relationship between the onset of hypertension and the activity of bevacizumab in Japanese metastatic colorectal cancer patients. Between July 2007 and December 2010, 36 patients (median age 66 years; 36-81 years) with metastatic colorectal cancer were assigned to receive bevacizumab in combination with either mFOLFOX6 (5-FU, levofolinate and oxaliplatin) or FOLFIRI (5-FU, levofolinate and irinotecan) at the Tokushima University Hospital. A patient who had increase by >20 mmHg in diastolic blood pressure or had increase to >150/100 mmHg or received antihypertensive treatment was defined as hypertensive. The objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were compared between the hypertensive group (n=10) and non-hypertensive group (n=26). ORR and DCR were 60.0% and 100%, respectively, in the hypertensive group and ORR and DCR were 23.1% and 80.8%, respectively, in the non-hypertensive group. These differences were statistically significant (p<0.05). The median PFS tended to be longer in the hypertensive group (65.0 weeks) than in the non-hypertensive group (40.0 weeks). Our data suggested that bevacizumab-induced hypertension may be predictive of the effect of bevacizumab in Japanese metastatic colorectal cancer patients.

Journal of the Pharmaceutical Society of Japan


Pharmacology in health food: Metabolism of quercetin in vivo and its protective effect against arteriosclerosis

Quercetin, a member of the bioflavonoids family, has been proposed to have anti-atherogenic, anti-inflammatory, and anti-hypertensive properties leading to the beneficial effects against cardiovascular diseases. It was recently demonstrated that quercetin 3-O-β-D-glucuronide (Q3GA) is one of the major quercetin conjugates in human plasma, in which the aglycone could not be detected. Although most of the in vitro pharmacological studies have been carried out using only the quercetin aglycone form, experiments using Q3GA would be important to discover the preventive mechanisms of cardiovascular diseases by quercetin in vivo. Therefore we examined the effects of the chemically synthesized Q3GA, as an in vivo form, on vascular smooth muscle cell (VSMC) disorders related to the progression of arteriosclerosis. Platelet-derived growth factor-induced cell migration and proliferation were inhibited by Q3GA in VSMCs. Q3GA attenuated angiotensin II-induced VSMC hypertrophy via its inhibitory effect on JNK and the AP-1 signaling pathway. Q3GA scavenged 1,1-diphenyl-2-picrylhydrazyl radical measured by the electron paramagnetic resonance method. In addition, immunohistochemical studies with monoclonal antibody 14A2 targeting the Q3GA demonstrated that the positive staining specifically accumulates in human atherosclerotic lesions, but not in the normal aorta. These findings suggest Q3GA would be an active metabolite of quercetin in plasma and may have preventative effects on arteriosclerosis relevant to VSMC disorders.


Effects of a 1.5 T time-varying magnetic field on cell volume regulation of bovine adrenal chromaffin cells in hyposmotic media.

Effects of a time-varying magnetic field on cell volume regulation by hyposmotic stress in cultured bovine adrenal chromaffin cells were examined. Through regulatory volume decrease (RVD), cell volume of chromaffin cells that were incubated in a hypotonic medium initially increased, reached a peak and finally recovered to the initial value. Two hour exposure to a magnetic field and addition of cytochalasin D increased peak value and delayed return to initial value. Intracellular F-actin contents initially decreased but returned to normal levels after 10 sec. Two hour exposure to the magnetic field and addition of cytochalasin D continuously reduced the F-actin content. Results suggest that exposure to the magnetic field stimulated disruption of the actin cytoskeleton and that the disruption delayed the recovery to the volume prior to osmotic stress.


Identification of TMEM45B as a protein clearly showing thermal aggregation in SDS-PAGE gels and dissection of its amino acid sequence responsible for this aggregation.

SDS-PAGE is one of the most powerful experimental techniques used for the separation of proteins, and most proteins are separated according to their molecular size by this technique. However, exceptional proteins showing abnormal behavior in SDS-PAGE gels are known to exist. Thermal aggregation, rarely observed with membrane proteins, is one of the exceptional behaviors of proteins during SDS-PAGE, but detailed characterization of this aggregation has not yet been achieved. In the present study, we found that a putative membrane protein, TMEM45B, very clearly showed properties of thermal aggregation when it was expressed in COS7 cells and subjected to SDS-PAGE. We dissected the region of TMEM45B responsible for this aggregation, and found that of the seven putative transmembrane domains, a region comprising the 4th to 7th ones was essential for the thermal aggregation properties. We also demonstrated that these transmembrane domains, 4th to 7th, of TMEM45B conferred thermal aggregation properties on other proteins, by fusing this amino acid sequence to target proteins. The molecular mechanism causing thermal aggregation by TMEM45B is still uncertain, but TMEM45B could be utilized as a nice model to show clear thermal aggregation in SDS-PAGE gels.


Altered dipeptidyl peptidase 4 activity during the progression of hyperinsulinemic obesity and islet atrophy in spontaneously late-stage type 2 diabetic rats.

Altered dipeptidyl peptidase-4 (DPP4) activity during the progression of late-stage type 2 diabetes was measured in Otsuka Long-Evans Tokushima fatty (OLETF) rats. Compared with OLETF rats subjected to 30% food restriction, food-satiated OLETF rats exhibited spontaneous hyperphagic obesity, insulin resistance, hyperglycemia, hyperinsulinemia, and increased plasma DPP4 activity during the early phase of the experiment (up to ∼30 wk). Subsequently, their plasma DPP4 activity as well as their body weight, body fat, and plasma insulin concentration declined to control levels during the late phase, resulting in excessive polyuria, proteinuria, dyslipidemia, pancreatic islet atrophy, hypoinsulinemia, and diabetes, which changed from insulin-resistant diabetes to hypoinsulinemic diabetes secondary to progressive islet insufficiency, and their fasting blood glucose level remained high. Since plasma DPP4 activity demonstrated significant positive correlations with body weight and the fasting plasma insulin level but not with the fasting blood glucose level during the late stage of diabetes, body fat and fasting plasma insulin levels may be useful factors for predicting the control of plasma DPP4 activity. In contrast, pancreatic DPP4 activity was significantly increased, and the expression of pancreatic insulin was significantly reduced in late-stage diabetic OLETF rats, suggesting that a relationship exists between the activation of pancreatic DPP4 and insulin depletion in pancreatic islet atrophy. In conclusion, it is suggested that plasma DPP4 activity changes in accordance with the progression of hyperinsulinemic obesity and pancreatic islet atrophy. DPP4 activity may play an important role in insulin homeostasis.


Role of dipeptidyl peptidase IV (DPP4) in the development of dyslipidemia: DPP4 contributes to the steroid metabolism pathway.

We previously reported that dipeptidyl peptidase IV (DPP4)-deficient rats were susceptible to dyslipidemia induced by streptozotocin (STZ). Hence, it is suggested that DPP4 is important for lipid metabolism. In this study, to verify the role of DPP4 in the development of dyslipidemia, we carried out a microarray analysis of the livers of STZ-treated wild-type and DPP4-deficient rats and showed that the expression levels of genes involved in metabolic processes (steroid metabolic processes and cellular lipid metabolic processes) were significantly altered by STZ treatment. In the wild-type rats, the expression of hydroxysteroid (17-beta) dehydrogenase 2 (Hsd7b2), which catalyzes sex steroid synthesis from cholesterol, was significantly increased by about 15-fold after STZ treatment; however, it did not change in the DPP4-deficient rats. In the STZ untreated group of DPP4-deficient rats, the expression levels of cytochrome P450, subfamily 51 (Cyp51) and sterol-C4-methyl oxidase-like (Sc4mol), which catalyze intermediate steps in cholesterol synthesis, were significantly elevated compared to those of other groups. Similar results were demonstrated in HuH7-cells after DPP4 overexpression or the addition of human sera containing DPP4. DPP4 is crucial for regulating the expression of factors related to steroid metabolism such as Cyp51, Sc4mol, and Hsd17b2, and DPP4 deficiency or inhibition may cause dyslipidemia.


EFFECTS OF EXPOSURE TO TIME-VARYING 1.5 T MAGNETIC FIELD ON VOLUME REGULATION OF BOVINE ADRENAL CHROMAFFIN CELLS

Proceedings of The Bioelectromagnetics Society 32nd Annual Meeting


Angiotensin II receptor blocker attenuates PDGF-induced mesangial cell migration in a receptor-independent manner

Clinical studies have shown that angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) are able to provide renoprotection independent of their blood pressure lowering effects. ARBs also are reported to suppress oxidative stress, inflammation and certain other cellular responses in a receptor-independent manner. We investigated the effects of an ARB, olmesartan, on the cell migration induced by platelet-derived growth factor (PDGF), a major mitogen involved in the pathogenesis of glomerulonephritis in rat mesangial cells (RMCs). Cell migration was determined by a modified Boyden chamber assay. The intracellular signalling pathway was examined by western blotting. AT1 receptor expression was knocked down by small interfering RNAs. The intracellular reactive oxygen species (ROS) was measured by using a fluorescent probe. The O(2)(.-) scavenging activities were studied by the electron paramagnetic resonance-spin trapping method. PDGF-induced cell migration was inhibited by olmesartan in AT1 receptor knockdown RMCs. Olmesartan attenuated big mitogen-activated protein (MAP) kinase 1 (BMK1) and Src activation by PDGF in AT1 receptor knockdown RMCs. PDGF-induced BMK1 activation was suppressed by the Src family tyrosine kinase inhibitors, indicating that Src exists upstream of BMK1. The NADPH oxidase inhibitors inhibited not only PDGF-induced BMK1 and Src activation but also RMC migration. The elevation in ROS generation induced by PDGF was decreased by olmesartan. Olmesartan displayed neither directly ROS scavenging activity nor the inhibition of ROS-mediated intracellular signalling in RMCs. Olmesartan attenuates ROS generation by PDGF, leading to the subsequent inhibition of Src/ BMK1/migration in an AT1 receptor-independent manner in RMCs.


Assessment of Pharmacokinetics of Midazolam for Dose Adjustment in Patients Undergoing Brain Hypothemia Therapy

脳低温療法時におけるミダゾラムの適正投与に向けて


Inhibitory effects of adiponectin on platelet-derived growth factor-induced mesangial cell migration

Adiponectin, an adipocyte-derived hormone, has been involved in metabolic syndrome, a known risk factor for the development of chronic kidney disease (CKD). Recent studies have demonstrated that plasma adiponectin levels are elevated when kidney function declines in patients with CKD. Excessive mesangial cell (MC) turnover is one of the important features of CKD. The aim of the present study is to elucidate the effects of adiponectin on platelet-derived growth factor (PDGF)-induced cell migration and intracellular signaling pathways, in cultured rat MCs (RMCs). PDGF-induced RMC migration was significantly inhibited by the pretreatment of adiponectin. Adiponectin alone had no effect on RMC migration. Big mitogen-activated protein (MAP) kinase 1 (BMK1), p38 MAP kinase, and Akt were activated by PDGF stimulation in a time- and concentration-dependent manner in RMC. Adiponectin alone did not affect BMK1, p38 MAP kinase, and Akt phosphorylations in RMC. PDGF-induced BMK1 and p38 MAP kinase phosphorylations were significantly attenuated by the pretreatment of adiponectin in RMCs. On the other hand, the phosphorylation of Akt by PDGF was not diminished by the pretreatment of adiponectin. Adiponectin had no effects on PDGF-receptor autophosphorylation by PDGF. We also confirmed that PDGF-induced RMC migration was significantly suppressed by siBMK1 transfection or SB203580, a p38 MAP kinase inhibitor. From these findings, it is implied that the elevated plasma adiponectin levels in patients with CKD might play a compensatory role aimed at counteracting renal dysfunction related to MC disorders.


抗菌薬，抗がん剤による薬物療法における乳酸菌生菌製剤の併用状況

抗菌薬，抗がん剤による薬物療法における乳酸菌生菌製剤の併用状況

Japanese Journal of Pharmaceutical Health Care and Sciences


現役薬剤師を対象とした漢方薬意識調査 --- ―効果的な漢方教育の実現に向けて―


Increased Plasma Dipeptidyl Peptidase IV (DPP IV) Activity and Decreased DPP IV Activity of Visceral But Not Subcutaneous Adipose Tissue in Impaired Glucose Tolerance Rats Induced by High-Fat or High-Sucrose Diet

Several studies have investigated whether dipeptidyl peptidase IV (DPP IV) activity is correlated to the severity of diabetes; however, it remains unclear. To investigate the roles of DPP IV activity in metabolic abnormalities, impaired glucose tolerance rats were produced using a high-fat (HF) or high-sucrose (HS) diet. HF diet-fed rats obviously exhibited impaired glucose tolerance, with increases in subcutaneous and epididymal fat mass, insulin resistance and dyslipidaemia. In rats fed a HS diet rather than a normal diet, lower body weight and fasting blood glucose were observed temporarily in the early period after HS diet feeding; however, impaired glucose tolerance was evoked to some extent with an increase in epididymal fat mass. Both HF and HS diet-fed rats showed significantly higher plasma DPP IV activity than normal diet-fed rats, in the order of HF diet>HS diet>normal diet. HF and HS diets did not significantly affect DPP IV activity and mRNA expression in the kidney. On the other hand, HF, but not HS, diet caused a significant decrease in DPP IV activity in the liver as compared to the control. Of note, both HF and HS diets caused a significant decrease in DPP IV activity in epididymal fat, even though they did not change DPP IV activity in subcutaneous fat. In conclusion, HF or HS diet-induced impaired glucose tolerance with visceral fat accumulation may be interrelated with increased plasma DPP IV activity and decreased DPP IV activity of visceral but not subcutaneous adipose tissue.


Quercetin Glucuronide Inhibits Cell Migration and Proliferation by Platelet-Derived Growth Factor in Vascular Smooth Muscle Cells

Many epidemiologic studies have reported that dietary flavonoids provide protection against cardiovascular disease. Quercetin, a member of the bioflavonoids family, has been proposed to have anti-inflammatory, anti-atherogenic, and anti-hypertensive properties leading to the beneficial effects against cardiovascular diseases. Recent studies demonstrated that orally administered quercetin appeared in plasma as glucuronide-conjugated forms in rats and humans. Therefore, we examined the effect of chemically synthesized quercetin glucuronide on platelet-derived growth factor (PDGF)-induced cell migration and kinase activation in cultured rat aortic smooth muscle cells (RASMCs). PDGF-induced RASMC migration was inhibited by quercetin 3-O-beta-D-glucuronide (Q3GA). Q3GA also attenuated PDGF-induced cell proliferation in RASMCs. PDGF activated extracellular-signal regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein (MAP) kinase, and Akt in RASMCs. PDGF-induced JNK and Akt activations were suppressed by Q3GA, whereas ERK1/2 and p38 MAP kinase activations were not affected. We also confirmed that PDGF-induced JNK and Akt activations were inhibited by antioxidants, N-acetylcysteine and diphenyleneiodonium chloride, in RASMCs. These findings suggest Q3GA would be an active metabolite of quercetin in plasma and may possess preventing effects for cardiovascular diseases relevant to vascular smooth muscle cell disorders.


Interrelationship of dipeptidyl peptidase IV (DPP IV) with the development of diabetes, dyslipidaemia and nephropathy: A streptozotocin-induced model using wild-type and DPP IV-deficient rats

We examined the role of dipeptidyl peptidase IV (DPP4) in the development of diabetes, dyslipidaemia and renal dysfunction induced by streptozotocin (STZ). F344/DuCrlCrlj rats, which lack DPP4 activity, and wild-type rats were treated with STZ. Plasma DPP4 activity and biochemical parameters were measured until 42 days after STZ treatment. At the end of the experiment, renal function and DPP4 expressions of the kidney, liver, pancreas and adipose tissues were determined. Increases in blood glucose, cholesterol and triglycerides were evoked by STZ in both rat strains; however, the onset of hyperglycaemia was delayed in DPP4-deficient rats as compared with wild-type rats. By contrast, more severe dyslipidaemia was observed in DPP4-deficient rats than in wild-type rats after STZ treatment. Plasma DPP4 activity increased progressively with time after STZ treatment in wild-type rats. The kidney of wild-type rats showed decreased DPP4 activity with increased Dpp4 mRNA after STZ treatment. In addition, kidney weight, serum creatinine and excreted amounts of urinary protein, glucose and DPP4 enzyme were enhanced by STZ. DPP4-deficient rats showed increased serum creatinine in accordance with decreased creatinine clearance as compared with wild-type rats after STZ treatment. In conclusion, plasma DPP4 activity increased after STZ treatment, positively correlating to blood glucose. DPP4-deficient rats were resistant to developing diabetes, while susceptible to dyslipidaemia and reduction of glomerular filtration rate by STZ. DPP4 activation may be responsible for hyperglycaemia, lipid metabolism and preservation of renal function.


Calcium and reactive oxygen species mediated Zn2+-induced apoptosis in PC12 cells

The release of excessive Zn(2+) from presynaptic boutons into extracellular regions contributes to neuronal apoptotic events, which result in neuronal cell death. However, the mechanisms of Zn(2+)-induced neuronal cell death are still unclear. Therefore, we investigated the dynamics of intracellular Zn(2+), calcium, and reactive oxygen species in PC12 cells. The addition of Zn(2+) produced cell death in a concentration- and time-dependent manner. (45)Ca(2+) influx occurred just after the treatment with Zn(2+), although subsequent hydroxyl radical ((*)OH) production did not begin until 3 h after Zn(2+) exposure. (*)OH production was significantly attenuated in Ca(2+)-free medium or by L-type Ca(2+) channel antagonist treatment, but it was independent of the intracellular Zn(2+) content. Dantrolene treatment had no protective effects against Zn(2+)-induced cell death. Treatment with N-acetyl-L-cysteine blocked (*)OH generation and subsequent cell death. These data indicate that Ca(2+) influx and subsequent (*)OH production are critical events in Zn(2+)-induced toxicity in PC12 cells.


徳島大学病院におけるTPN処方設計支援ソフトの使用評価と改良

徳島大学病院におけるTPN処方設計支援ソフトの使用評価と改良

Fluid therapy is a fundamental treatment for almost all inpatients, and nutritional therapy is the most important type of such therapy. Currently, total parenteral nutrition (TPN) is widely used to provide complete nutritional support but 30-40% of TPN recipients are considered to in a malnourished state due to inappropriate TPN prescriptions. Computer-assisted TPN prescription systems are thought to be useful to clinical professionals in solving this problem because they can perform complicated calculations that make it easy to draw up correct TPN prescriptions. So, we made a prototype system for aiding the preparation of TPN prescriptions based on Microsoft^[ !R] EXCEL and it was tested by physicians, pharmacists, dietitians and nurses engaged in TPN therapy at Tokushima University Hospital. We also had them fill out a questionnaire on the system in which they rated it for ease of operation and usefulness according to a scoring system in which 5 indicated full marks. Our Computer-Assisted TPN Prescription System was improved on the basis of the questionnaire results and is now being effectively used by the nutrition support team (NST) in Tokushima University Hospital.


Effects of a time-varying strong magnetic field on transient increase in Ca2+ release induced by cytosolic Ca2+ in cultured pheochromocytoma cells

Exposure of pheochromocytoma (PC 12) cells to a time-varying 1.51 T magnetic field inhibited an increase in the intracellular Ca2+ concentration ([Ca2+]i) induced by addition of caffeine to Ca(2+)-free medium. This inhibition occurred after a 15-min exposure and was maintained for at least 2 h. [Ca2+]i sharply increased in cells loaded with cyclic ADP-ribose, and 2-h exposure significantly suppressed the increase. Addition of ATP induced a transient increase in intracellular Ca2+ release mediated by IP3 receptor, and this increase was strongly inhibited by the exposure. Results indicated that the magnetic field exposure strongly inhibited Ca2+ release mediated by both IP3 and ryanodine receptors in PC 12 cells. However, thapsigargin-induced Ca2+ influx (capacitative Ca2+ entry) across the cell membrane was unaffected. The ATP content was maintained at the normal level during the 2-h exposure, suggesting that ATP hydrolysis was unchanged. Therefore, Mg2+ which is known to be released by ATP hydrolysis and inhibit intracellular Ca2+ release may not relate the exposure-caused inhibition. Eddy currents induced in culture medium appear to change cell membrane properties and indirectly inhibit Ca2+ release from endoplasmic reticulum and other Ca2+ stores in PC 12 cells.

Biochimica et Biophysica Acta (BBA) - General Subjects


Dual effects of endothelin-1 (1-31): induction of mesangial cell migration and facilitation of monocyte recruitment through monocyte chemoattractant protein-1 production by mesangial cells

We previously found that human chymase selectively cleaves big endothelin-1 (ET-1) at the Tyr31-Gly32 bond and produces 31-amino acid endothelins, ET-1 (1-31), without any further degradation products. In this study, we investigated the effect of ET-1 (1-31) on the migration of cultured rat mesangial cells (RMCs) and on cells of the human monocytic cell line, THP-1. In addition, we examined the interaction between RMCs and THP-1 cells using conditioned media from ET-1 (1-31)-stimulated RMCs. ET-1 (1-31) caused an increase in RMC migration in a concentration-dependent manner, and the degree of increase was similar to those by ET-1 and angiotensin II (All). The ET-1 (1-31)-induced increase in RMC migration was inhibited by BQ123, an endothelin ETA receptor antagonist, but not by BQ788, an endothelin ETB receptor antagonist. ET-1 (1-31) alone did not cause significant migration of THP-1 cells. However, significant recruitment of THP-1 cells was observed with conditioned media taken from ET-1 (1-31)-stimulated RMCs. The conditioned media-induced migration of THP-1 cells was inhibited by BQ123, but not by BQ788. Western blotting analysis of the lysate of RMCs revealed that the expression of monocyte chemoattractant protein-1 (MCP-1) protein in RMCs was increased by treatment with ET-1 (1-31). The addition of neutralizing antibody for MCP-1 to the medium inhibited the migration of THP-1 cells induced by conditioned media from ET-1 (1-31)-stimulated RMCs. These findings suggest that ET-1 (1-31) play a role in glomerulonephritis (GN) via dual effects that directly cause the migration of mesangial cells (MCs) and may be responsible for the recruitment of mononuclear cells mediated through the activation of MCs. Since human chymase has been reported to be involved in glomerular disease, ET-1 (1-31) may be among the mediators.


Inhibitory action of novel arginine derivative on catecholamine secretion evoked by acetylcholine from cultured bovine adrenal chromaffin cells

A novel product, 4-amino-5-guanidinopentanoic acid 15-[(4-aminobutyl)-3-aminopropylcarbamoyl] pentadecyl ester (Arg-HSA-Spm), was synthesized based on ptilomycalin A, which is one of the extracts from marine sponge. Arg-HSA-Spm contains arginine in its chemical structure. The pharmacological action of Arg-HSA-Spm on catecholamine secretion from cultured bovine adrenal chromaffin cells was examined. Arg-HSA-Spm inhibited catecholamine secretion stimulated by the physiological secretagog acetylcholine. This inhibitory action of Arg-HSA-Spm on catecholamine secretion induced by 10(-4) M acetylcholine was dose-dependent from 10(-8) M to 10(-5) M. In the presence of 3 x 10(-7) M Arg-HSA-Spm, the stimulation of catecholamine secretion observed by increasing acetylcholine up to 10(-3) M did not reach the maximal level observed without Arg-HSA-Spm. Arg-HSA-Spm at 10(-5) M suppressed both the increase in intracellular free Ca2+ level and the influx of 45Ca2+ induced by 10(-4) M acetylcholine. The Arg-HSA-Spm-induced suppression of intracellular free Ca2+ level, the influx of 45Ca2+ and catecholamine secretion were not observed in the presence of extracellular K+ at 56 mM. The results presented in this study suggested that Arg-HSA-Spm may inhibit the influx of extracellular Ca2+ into the cells, probably through its blocking action related to acetylcholine receptors, resulting in the inhibition of catecholamine secretion in adrenal chromaffin cells.


シクロオキシゲナーゼII阻害薬のヒト血小板凝集に及ぼす影響

シクロオキシゲナーゼII阻害薬のヒト血小板凝集に及ぼす影響


Determination of plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy subjects and patients with atherosclerosis.

We previously found that human chymase cleaves big endothelins at the Tyr31-Gly32 bond and produces 31-amino-acid endothelins, endothelins(1-31). Endothelin-1(1-31) has been isolated from a number of human organs, including the heart and lungs. As endothelin-1 has been shown to play a significant role in the paracrine regulation of cardiovascular functions in humans, it is possible that endothelin-1(1-31) may also exhibit biological activity on human tissues. We previously reported that synthetic endothelin-1(1-31) exhibits a number of physiological actions on cultured cells in vitro. In the present study, we investigated the plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy subjects and compared them with those in patients with cardiovascular diseases. Endothelin-1(1-31) and endothelin-1 in human plasma was measured using a sandwich-enzyme-immunoassay system, which was recently described for measurement of endothelin-1(1-31). The plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy volunteers were 19.24 +/- 5.70 and 15.54 +/- 4.45 pg/ml (n = 5), respectively. We also measured plasma concentrations of endothelin-1(1-31) and endothelin-1 before and after surgery in patients with abdominal aortic aneurysms. Before surgery, plasma concentrations of endothelin-1(1-31) and endothelin-1 in these patients were higher than those in healthy individuals. After surgery, both endothelin-1(1-31) and endothelin-1 in plasma decreased to levels similar to those of healthy subjects. This suggests that endothelin-1(1-31) may have similar physiological significance to endothelin-1 in patients with atherosclerosis.


Effects of Time-Varying Strong Magnetic Fields on Rerease of Cytosolic Free Ca2+ from Intracellular Stores in Cultured Bovine Adrenal Chromaffin Cells

This study was made to explain the mechanisms for the effects of exposure to a time varying 1.51 T magnetic field on the intracellular Ca(2+) signaling pathway. The exposure inhibited an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) in bovine chromaffin cells induced by addition of bradykinin (BK) to a Ca(2+) free medium. The exposure did not change BK induced production of inositol 1,4,5-trisphosphate (IP(3)). [Ca(2+)](i) was markedly increased in IP(3) loaded cells, and this increase was inhibited by the magnetic field exposure. A similar increase in [Ca(2+)](i) by other drugs, which stimulated Ca(2+) release from intracellular Ca(2+) stores, was again inhibited by the same exposure. However, transmembrane Ca(2+) fluxes caused in the presence of thapsigargin were not inhibited by the magnetic field exposure in a Ca(2+) containing medium. Inhibition of the BK induced increase in [Ca(2+)](i) by the exposure for 30 min was mostly recovered 1 h after exposure ended. Our results reveal that the magnetic field exposure inhibits Ca(2+) release from intracellular Ca(2+) stores, but that BK bindings to BK receptors of the cell membrane and intracellular inositol IP(3) production are not influenced.


Effects of losartan in combination with or without exercise on insulin resistance in Otsuka Long-Evans Tokushima Fatty rats.

Hypertension often complicates type 2 diabetes mellitus, and angiotensin converting enzyme inhibitor treatment has been shown to improve insulin resistance in such cases. However, the effect of angiotensin II type-1 (AT(1)) receptor antagonists on insulin resistance is still controversial. To gain further information on this effect, we examined the effect of losartan on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. Losartan administration alone lowered systolic blood pressure, but did not improve oral glucose tolerance test or insulin resistance in OLETF rats. However, the administration of losartan with exercise significantly improved both systolic blood pressure and insulin resistance relative to control OLETF rats. On the other hand, losartan treatment, regardless of exercise, increased glucose uptake in excised soleus muscle and fat cells. To explore the beneficial effect of losartan on skeletal muscle glucose uptake, we examined intracellular signaling of soleus muscle. Although Akt activity and glucose transporter type 4 (GLUT4) expressions were not affected by losartan with or without exercise, extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein (MAP) kinase activities were increased by both interventions. These results indicate that angiotensin AT(1) receptor antagonist improved local insulin resistance, but not systemic insulin resistance. These findings may explain the controversy over the effect of angiotensin AT(1) receptor antagonists on insulin resistance in clinical use. The enhancing effect of angiotensin AT(1) receptor antagonist on skeletal muscle glucose uptake may be attributable to MAP kinase activation or other mechanisms rather than phosphatidylinositol 3-kinase activation.


Long-term regulation of catecholamine formation by ouabain in cultured bovine adrenal cromaffin cells.

The long-term effects of ouabain, an inhibitor of Na+/K+ -ATPase, on catecholamine formation in cultured bovine adrenal chromaffin cells were examined. The increase in [14C]catecholamine formation from [14C]tyrosine induced by ouabain was dependent on incubation time, and its maximal effect was observed after incubation for 8 h. The stimulatory effect of ouabain was concentration dependent (10-300 nM), causing maximal stimulation at 300 nM. The formation of [14C]catecholamines induced by ouabain was not increased by incubation with [14C]DOPA instead of [14C]tyrosine. Ouabain-induced [14C]catecholamine formation was influenced by decreases in extracellular Ca2+ concentration, but not by the presence of cycloheximide or actinomycin D. These results suggested that ouabain stimulates continuous activation of hydroxylation of tyrosine through a Ca2+ -dependent mechanism in cultured bovine adrenal chromaffin cells.


Dopamine Clearance During Dopamine Infusion in Infants and Children After Cardiac Surgery


Stimulatory effect of enkephalines on calcium efflux from bovine adrenal chromaffin cells in culture.


Possible role of bradykinin on stimulus-secretion coupling in adrenal chromaffin cells

Nonapeptide bradykinin is known to be a central nervous system neurotransmitter and to play a role in regulation of neuronal function. However, few details are known of the function of its peptide on stimulus-secretion coupling in neuronal cells. In this article, the role of bradykinin on catecholamine biosynthesis, secretion and Ca2+ movement in adrenal chromaffin cells as a model for catecholamine-containing neurons are examined. Bradykinin receptors are classified as B1 and B2 receptor subtypes. These receptors are present on the adrenal chromaffin cell membrane. Bradykinin increases the influx of Ca2+ and the turnover of phosphoinositide through the stimulation of bradykinin B2 receptor. The secretion of catecholamine from the cells is initiated by the raise of [Ca2+]i. An increase in [Ca2+]i and production of diacylglycerol stimulate the activation of calcium-dependent protein kinases. These kinases stimulate the activation of tyrosine hydroxylase, a rate-limiting enzyme in the biosynthesis of catecholamine. Otherwise, bradykinin increases Ca2+ efflux from the cells through the stimulation of the bradykinin-B2 receptor. This action may be explained by an extracellular Na(+)-dependent mechanism, probably through acceleration of Na+/Ca2+ exchange. It is interesting that bradykinin, which stimulates the biosynthesis and secretion of catecholamine in adrenal chromaffin cells, plays a role in the termination of calcium-signal transduction through the stimulation of Ca2+ efflux from the cells.

The Journal of Medical Investigation : JMI


Nitric oxide-forming reactions of the water-soluble nitric oxide spin-trapping agent, MGD.


Plasma levels of free and sulfoconjugated catecholamines in patients with atherosclerosis.


Endothelin-1 stimulates sodium-dependent calcium efflux from bovine adrenal chromaffin cells in culture.


Effects of a time-varying strong magnetic field on transient increase in cytosolic free-Ca2+ induced by bradykinin in cultured bovine adrenal chromaffin cells.


Changes in plasma free and sulfoconjugated catecholamines during the perioperative period of cardiac surgery:Effect of continuous infusion of dopamine.


Effect of evodiamine on catecholamine secretion from bovine adrenal medulla.

The effect of evodiamine on catecholamine secretion from bovine adrenal medulla was investigated. Evodiamine, a bioactive component isolated from dry unripened fruit of Evodia rutaecarpa Bentham, was found to stimulate the secretion of catecholamine from perfused bovine adrenal medulla at a concentration of 10 microM and its effect persisted for at least 30 min. This stimulatory effect of evodiamine was abolished by omission of Ca2+ from the perfusion fluid. Evodiamine (0.1-10 microM) markedly enhanced the secretion of catecholamine from the adrenal medulla induced by acetylcholine (100 microM or high K+(56 mM). The secretion of catecholamine was promptly enhanced by acetylcholine or high K+, but returned to the control level on treatment for 20 min. However, when evodiamine was added to the perfusion fluid after acetylcholine or high K+ stimulation for 10 min, the secretion of catecholamine again increased greatly. These results indicate that evodiamine not only stimulated the secretion of catecholamine from bovine adrenal medulla but also reversed insensitivity of these cells to acetylcholine or high K+ stimulation.


Potentiation of histamine-induced catecholamine secretion by ouabain in cultured bovine adrenal chromaffin cells is dependent on calcium and sodium influx.


Serotonin increases Na+-dependent Ca2+ efflux from bovin sdrenal chromaffin cells in culture.


Atrial natriuretic peptide stimulates Na+-dependent Ca2+ effulux from freshly isolated adult rat cardiomyocytes.


マラソン前後における血中遊離型および硫酸抱合型カテコラミンの変動

マラソン前後における血中遊離型および硫酸抱合型カテコラミンの変動


Changes in plasma free and sulfoconjugated catecholamines before and after acute physical exercise:Experimental and clinical studies.


つるぎ町一宇地区の民間薬調査

つるぎ町一宇地区の民間薬調査


病院薬剤部・薬局の整備，構造，機能基準の改定に関する研究(最終報告)

病院薬剤部・薬局の整備，構造，機能基準の改定に関する研究(最終報告)

Journal of Japnese Society of Hospital Pharmacists


NSAIDSがアスピリンの抗血小板作用に与える影響の検討

NSAIDSがアスピリンの抗血小板作用に与える影響の検討


三好市東祖谷地区の民間薬調査

三好市東祖谷地区の民間薬調査


Effect of time-varying magnetic field on cell volume regulation of adrenal chromaffin cells

副賢クロマフィン細胞の細胞容積調節に及ぼす変動磁界の影響

The Journal of Japan Biomagnetism and Bioelectromagnetics Society


Surveillance and the Approach for the Proper Use of Antibiotics at Tokushima University Hospital

徳島大学医学部附属病院における抗菌薬適正使用の取り組みと使用状況

The working committee for the proper use of antibiotics was organized at Tokushima University Hospital in March 2002, and the institutional guidelines for the selection and use of antibiotics were established. The infection control team (ICT) also started monitoring the use of particular antibiotics, including third- and fourthgeneration cephalosporins, calbapenems and anti-MRSA antibiotics, and reported on their use in August 2002. To assess these activities, we examined the status of antibiotic use for injections and compared our findings with the previous data. The results were as follows : 1) the reports required were presented in 47% of the total antibiotics used ; 2) after starting the surveillance, the use of the third- and fourth-generation cephalosporins and calbapenems shifted to the first- and second-generation drugs, while the use of anti-MRSA drugs clearly decreased ; 3) these changes resulted in a savings of more than two million yen in medical expenditures in a month. These results suggest that closely monitoring the use of antibiotics may thus be beneficial not only for promoting the proper use of antibiotics but also for reducing overall medical costs.

Japanese Journal of Pharmaceutical Health Care and Sciences