Publications by authors named "Shigeru Yoshida"

104 Publications

Annual body mass index gain and risk of hypertensive disorders of pregnancy in a subsequent pregnancy.

Sci Rep 2021 11 18;11(1):22519. Epub 2021 Nov 18.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.

Weight gain during interpregnancy period is related to hypertensive disorders of pregnancy (HDP). However, in interpregnancy care/counseling, the unpredictability of the timing of the next conception and the difficulties in preventing age-related body weight gain must be considered while setting weight management goals. Therefore, we suggest considering the annual change in the body mass index (BMI). This study aimed to clarify the association between annual BMI changes during the interpregnancy period and HDP risk in subsequent pregnancies. A multicenter retrospective study of data from 2009 to 2019 examined the adjusted odds ratio (aOR) of HDP in subsequent pregnancies. The aORs in several annual BMI change categories were also calculated in the subgroups classified by HDP occurrence in the index pregnancy. This study included 1,746 pregnant women. A history of HDP (aOR, 16.76; 95% confidence interval [CI], 9.62 - 29.22), and annual BMI gain (aOR, 2.30; 95% CI, 1.76 - 3.01) were independent risk factors for HDP in subsequent pregnancies. An annual BMI increase of ≥ 1.0 kg/m/year was related to HDP development in subsequent pregnancies for women without a history of HDP. This study provides data as a basis for interpregnancy care/counseling, but further research is necessary to validate our findings and confirm this relationship.
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http://dx.doi.org/10.1038/s41598-021-01976-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602630PMC
November 2021

Prevalence and risk factors of labor-onset hypertension: A multicenter study in Japan.

Pregnancy Hypertens 2021 Dec 4;26:48-53. Epub 2021 Sep 4.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objectives: To investigate the prevalence and risk factors of labor-onset hypertension (LOH), defined as hypertension first detected during labor among women without hypertension prior to admission for labor.

Study Design: In this multicenter retrospective study, clinical data of women who delivered vaginally at term between 2012 and 2018 were collected from 12 primary maternity care units. Blood pressure was measured at five time points from admission to 2 h postpartum in a total of 30,129 normotensive women at the last prenatal check-up. LOH was defined as systolic blood pressure (SBP) of ≥ 140 mmHg or diastolic blood pressure (DBP) of ≥ 90 mmHg during the first to fourth stages of labor.

Main Outcome Measures: Multivariate regression analyses were conducted to evaluate the risk factors of LOH and severe LOH (SBP of ≥ 160 mmHg or DBP of ≥ 110 mmHg).

Results: Among the 30,129 women, 8,565 (28.4%) presented with LOH and 734 (2.4%) with severe LOH. The prevalence of LOH was the highest at the second stage of labor (21.7%) and decreased rapidly after delivery. The independent risk factors of LOH were maternal age of ≥ 35 years, pre-pregnancy body mass index of ≥ 25 kg/m, and pregnancy weight gain of ≥ 15 kg.

Conclusion: LOH is common, with approximately one in four women experiencing LOH during labor and early postpartum. Meanwhile, severe LOH occurred in 2.4% of the pregnancies. Closer blood pressure monitoring during labor may enable obstetric caregivers to recognize LOH in a timely manner and reduce maternal adverse outcomes, such as eclampsia and stroke.
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http://dx.doi.org/10.1016/j.preghy.2021.08.118DOI Listing
December 2021

Manual removal of the placenta and postpartum hemorrhage: A multicenter retrospective study.

J Obstet Gynaecol Res 2021 Nov 5;47(11):3867-3874. Epub 2021 Sep 5.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Aim: In postpartum women, retained placenta is diagnosed in the absence of signs of placental separation and expulsion, and requires manual removal of the placenta (MROP). MROP may lead to massive hemorrhage, hemodynamic instability, and the need for emergency interventions including blood transfusion, interventional radiology, and hysterectomy. In this study, we aimed to identify the risk factors for retained placenta requiring MROP after vaginal delivery and postpartum hemorrhage (PPH) following MROP.

Methods: A multicenter retrospective study was performed using data from women who delivered at term between 2010 and 2018 at 13 facilities in Japan. Of 36 454 eligible women, 112 women who required MROP were identified. Multivariate logistic regression analyses were conducted to evaluate the risk factors for retained placenta and PPH following MROP.

Results: A history of abortion, assisted reproductive technology (ART), instrumental delivery, and delivery of small-for-gestational-age infant were independent risk factors for MROP (adjusted odds ratios [95% confidence intervals]: 1.93 [1.28-2.92], 8.41 [5.43-13.05], 1.80 [1.14-2.82], and 4.32 [1.97-9.48], respectively). ART was identified as an independent risk factor for PPH (adjusted odds ratio [95% confidence interval]: 6.67 [2.42-18.36]) in patients who underwent MROP.

Conclusion: ART pregnancies significantly increased the risk of retained placenta requiring MROP and PPH. Our results suggest that clinicians need consider patient transfer to a higher-level facility and preparation of sufficient blood products before initiating MROP in cases of ART pregnancies. Our study may assist in identifying high-risk women for PPH before MROP and in guiding treatment decisions, especially in facilities without a blood bank.
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http://dx.doi.org/10.1111/jog.15004DOI Listing
November 2021

Pre-pregnancy sleep duration and postpartum depression: a multicenter study in Japan.

Arch Womens Ment Health 2021 Jul 13. Epub 2021 Jul 13.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Postpartum depression (PPD) is as a major public health issue and clinical priority worldwide. This study aimed to investigate the association between pre-pregnancy sleep duration and PPD. A multicenter retrospective study was conducted using clinical data of women who delivered at term between 2014 and 2018 at 12 maternity care hospitals in Japan. A total of 15,314 women were stratified into five groups according to their pre-pregnancy sleep duration: < 6, 6-7, 7-8, 8-9, and ≥ 9 h. Univariate and multivariate regression analyses were conducted to determine whether pre-pregnancy sleep duration affects the Edinburgh Postnatal Depression Scale (EPDS) scores at 1 month postpartum. We also evaluated whether the risk for PPD differs between primipara and multipara women classified according to pre-pregnancy sleep duration. The adjusted odds ratio for high EPDS scores (≥ 9) among women who slept for < 6 h and 6-7 h was 2.08 (95% confidence interval [CI]: 1.60-2.70) and 1.41 (95% CI: 1.18-1.68), respectively, relative to that in women with 7-8 h of sleep as the reference group. A 1-h increase in sleep duration was associated with an approximately 14% reduction in the risk for high EPDS scores. The association between short sleep duration and high EPDS scores was more remarkable in multipara women than in primipara women. Short pre-pregnancy sleep duration is associated with high EPDS scores, and this association is more significant in multipara women than in primipara women. Our findings emphasize the importance of collecting information on pre-pregnancy sleep duration to identify women at a high risk for PPD.
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http://dx.doi.org/10.1007/s00737-021-01136-1DOI Listing
July 2021

Platelet counts during normal pregnancies and pregnancies complicated with hypertensive disorders.

Pregnancy Hypertens 2021 Jun 5;24:73-78. Epub 2021 Mar 5.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objectives: To determine the trajectories of platelet counts and the prevalence of gestational thrombocytopenia (<150 × 10/L) during normal pregnancies and pregnancies with complications, such as hypertensive disorders of pregnancy (HDP), preeclampsia, and fetal growth restriction (FGR).

Study Design: A multicenter retrospective study was conducted using laboratory data on women who delivered term singletons at 11 primary maternity care units between 2011 and 2018 (n = 35,045), and non-pregnant women who underwent a medical check-up between 2016 and 2019 (n = 61,189). After 1:1 matching, 28,073 pregnant women and 28,073 non-pregnant women were selected for analysis.

Main Outcomes Measures: The trajectories of platelet counts and prevalence of gestational thrombocytopenia were evaluated in normal pregnant women, pregnant women with complications, and non-pregnant women.

Results: The platelet counts declined throughout pregnancy, with the nadir occurring on postpartum day 1. The platelet counts recovered to the level of the non-pregnant state at postpartum 2-7 days. The mean platelet counts at postpartum day 1 decreased by an estimated 19.8% and 9.7% compared to those in the non-pregnant state and first trimester, respectively. The prevalence of gestational thrombocytopenia in normal pregnant women at 37-41 gestational weeks and in pregnant women with complications of HDP, preeclampsia, and FGR were 6.1%, 7.3%, 17.5%, and 7.7%, respectively.

Conclusion: Platelet counts declined throughout pregnancy and recovered to the level of the non-pregnant state in the early postpartum period. Gestational thrombocytopenia is common during normal pregnancy, and its prevalence is significantly higher in women with preeclampsia.
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http://dx.doi.org/10.1016/j.preghy.2021.02.013DOI Listing
June 2021

Liver transaminase levels during pregnancy: a Japanese multicenter study.

J Matern Fetal Neonatal Med 2021 Feb 28:1-7. Epub 2021 Feb 28.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Introduction: There are conflicting reports on the effect of pregnancy on liver transaminase (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) levels. In this study, we sought to investigate the trajectories of AST and ALT levels during normal pregnancy and to compare them with AST and ALT levels of matched nonpregnant controls.

Materials And Methods: Our multicenter retrospective study included 34,396 women who delivered at term at 12 primary maternity care units between January 2011 and December 2018 and 57,152 nonpregnant women younger than 45 years who received a medical checkup between 2016 and 2019. After matching at a ratio of 1:1 for adjustment of several factors (age, weight, and height), a total of 30,460 normal pregnant women and 30,460 nonpregnant women were selected for this study. We measured serum AST and ALT levels during each trimester and the postpartum period to compare with those of the nonpregnant women.

Results: The ALT level began to decrease in the first half of the third trimester and was lowest in the second half of third trimester and at postpartum day 1 (median [interquartile range]: 8 [6-11] U/L, 8 [6-10] U/L, respectively). The decline reversed and returned to the level of a nonpregnant state by postpartum days 2-7. The AST level remained unchanged regardless of pregnancy. The prevalence of abnormal liver transaminases (AST >40 U/L and ALT >40 U/L) was <1% at third trimester; however, it increased to 3-5% on postpartum days 2-7.

Conclusions: The ALT level was lower during pregnancy compared with nonpregnant women matched for several factors, whereas the AST level remained unchanged during pregnancy. Understanding the trajectories of AST and ALT levels during pregnancy may facilitate early recognition and diagnosis of impaired liver function, including liver disease and pregnancy complications that affect liver transaminases, such as pre-eclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome.
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http://dx.doi.org/10.1080/14767058.2021.1892633DOI Listing
February 2021

Maternal low birth weight and hypertensive disorders of pregnancy.

Pregnancy Hypertens 2021 Mar 30;23:5-10. Epub 2020 Oct 30.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objectives: To investigate the association between maternal own low birth weight (<2500 g) and subsequent risks for hypertensive disorders of pregnancy (HDP) and preeclampsia.

Study Design: A multicenter retrospective study was conducted using clinical data from 12 primary maternity care units from 2012 to 2018. A total of 17,119 women with information about their own birth weight, who delivered at term, were subdivided into four groups according to maternal birth weights [(<2500, 2500-3499, 3500-3999, and ≥4000) g].

Main Outcome Measures: Multivariate regression analyses were conducted to evaluate the risks for HDP and preeclampsia among women born with low birth weight compared with women born with a birth weight of 2500-3499 g. We evaluated these risks, stratified by pre-pregnancy BMI or their infants' birth weight categories.

Results: Maternal low birth weight was an independent risk factor for HDP after adjustment for several covariates, but not for preeclampsia. A 100-g increase in maternal birth weight was associated with a 3% risk reduction for HDP. Additionally, women born with low birth weight had the highest risk for HDP among those with a pre-pregnancy BMI of ≥25 kg/m. Conversely, women born with high birth weight (≥4000 g) had the highest risk for preeclampsia if they complicate with fetal growth restrictions.

Conclusion: Women born with low birth weight had an increased risk for HDP. Collection of information on maternal birth weight may facilitate the prediction of HDP and patients' self-awareness of such risk, allowing the modification of lifestyle factors associated with HDP.
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http://dx.doi.org/10.1016/j.preghy.2020.10.010DOI Listing
March 2021

Shock Index and Postpartum Hemorrhage in Vaginal Deliveries: A Multicenter Retrospective Study.

Shock 2021 03;55(3):332-337

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Introduction: Shock index (SI), calculated by dividing heart rate by systolic blood pressure, is used to detect hemodynamic instability and hypovolemia. In obstetric practice, limited evidence is available regarding its usefulness in detecting postpartum hemorrhage (PPH). We aimed to evaluate the usefulness of SI in detecting PPH in vaginal deliveries using clinical data from 12 primary maternity care units in Japan.

Material And Methods: In this multicenter retrospective study, a total of 30,820 women who delivered vaginally at term at 12 primary maternity care units from January 2012 to December 2018 were included. Systolic and diastolic blood pressures and heart rate were measured at five different time points from admission to postpartum 2 h, and postpartum blood loss was measured. We evaluated the trend of average SI and the performance of each vital sign for detection of PPH.

Results: The trend of average SI during labor and the immediate postpartum period was approximately 0.7 in women with blood loss of <500 mL. SI from the time of delivery of the placenta increased with an increase in blood loss. SI had the highest area under the receiver operating characteristic curve of 0.699 [95% confidence interval (CI), 0.682-0.716] and 0.758 (95% CI, 0.729-0.788) for PPH of ≥1,000 and ≥1,500 mL, respectively. However, both sensitivity of SI (1.0) for PPH (≥1,000 mL; 29.9%, and ≥1,500 mL; 40.5%, respectively) and correlation between maximum SI and blood loss (coefficient of correlation, 0.263) were low.

Conclusions: SI is a better parameter for PPH detection in vaginal deliveries than other vital signs. However, clinical judgment must incorporate other vital signs and symptoms associated with hypovolemic shock due to the low sensitivity of SI.
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http://dx.doi.org/10.1097/SHK.0000000000001634DOI Listing
March 2021

Safety and pharmacokinetic profiles of MGS0274 besylate (TS-134), a novel metabotropic glutamate 2/3 receptor agonist prodrug, in healthy subjects.

Br J Clin Pharmacol 2020 11 10;86(11):2286-2301. Epub 2020 Jun 10.

Taisho Pharmaceutical Co., Ltd., Tokyo, Japan.

Aims: The safety and pharmacokinetics of single and multiple doses of a novel mGlu receptor agonist prodrug, MGS0274 besylate (TS-134), were investigated in healthy subjects.

Methods: Phase 1 single-ascending dose (5-20 mg) and multiple-ascending dose titration (5-80 mg) studies were conducted in healthy male and female subjects. Both studies were randomized, double-blinded and placebo-controlled. In one cohort of single-ascending dose study (10 mg), concentrations of MGS0008, the active compound, in the cerebrospinal fluid (CSF) were measured for up to 24 hours postdose.

Results: Following single and multiple oral administrations, MGS0274 was rapidly absorbed and extensively converted into MGS0008, which reached a maximum concentration (C ) in plasma within 4 hours postdose and declined with a terminal half-life (t ) of around 10 hours. Plasma exposure to MGS0274 was minimal, accounting for approximately 3% of the area under the concentration-time curve (AUC) of MGS0008. Plasma C and AUC of MGS0008 at steady state increased dose proportionally (5-80 mg). MGS0008 penetrated into CSF, with a CSF-to-plasma C ratio of 3.66%, and was eliminated with a t of approximately 16 hours. The most frequent treatment-emergent adverse events observed following single and multiple oral administration included headache, nausea, somnolence, dizziness and vomiting.

Conclusion: TS-134 is orally bioavailable in humans and converts rapidly and extensively to MGS0008, which exhibits good CSF penetration. Orally administered TS-134 was safe and generally well-tolerated; hence, TS-134 is a promising candidate for further clinical development for the treatment of disorders in which glutamatergic abnormalities are involved, such as schizophrenia.
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http://dx.doi.org/10.1111/bcp.14331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576618PMC
November 2020

Genetic deletion of Ca3.2 T-type calcium channels abolishes HS-dependent somatic and visceral pain signaling in C57BL/6 mice.

J Pharmacol Sci 2019 Jul 30;140(3):310-312. Epub 2019 Jul 30.

Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan. Electronic address:

We tested whether genetic deletion of Ca3.2 T-type Ca channels abolishes hydrogen sulfide (HS)-mediated pain signals in mice. In Ca3.2-expressing HEK293 cells, NaS, an HS donor, at 100 μM clearly increased Ba currents, as assessed by whole-cell patch-clamp recordings. In wild-type C57BL/6 mice, intraplantar and intracolonic administration of NaS evoked mechanical allodynia and visceral nociceptive behavior, respectively, which were abolished by TTA-A2, a T-type Ca channel blocker. In Ca3.2-knockout mice of a C57BL/6 background, NaS caused neither somatic allodynia nor colonic nociception. Our study thus provides definitive evidence for an essential role of Ca3.2 in HS-dependent somatic and colonic pain.
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http://dx.doi.org/10.1016/j.jphs.2019.07.010DOI Listing
July 2019

Serological screening of immunoglobulin M and immunoglobulin G during pregnancy for predicting congenital cytomegalovirus infection.

BMC Pregnancy Childbirth 2019 Jun 20;19(1):205. Epub 2019 Jun 20.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Cytomegalovirus (CMV) is one of the most frequent pathogens for congenital infections. Most cases of congenital CMV infection (cCMV) are asymptomatic at birth, but sensorineural hearing loss (SNHL) or neurodevelopmental delay can appear later in childhood. This prospective study examined the practicability of serological screening for anti-CMV immunoglobulin (Ig) G and anti-CMV IgM in pregnant women.

Methods: A total of 11,753 pregnant women were examined for CMV IgG and CMV IgM during the first or second trimester. When IgM was positive, IgG was reevaluated more than two weeks later. When IgG was negative, IgG was reevaluated in the second or third trimester. All neonates from mothers with positive/borderline IgM or IgG seroconversion underwent polymerase chain reaction assay for CMV using urine samples to diagnose cCMV. Levels of IgG and IgM were compared between mothers with and without cCMV. Receiver operating characteristic (ROC) curves for IgM titers were analyzed.

Results: Eight of 500 neonates (1.6%) born from mothers with positive IgG and positive IgM, and 3 of 13 neonates (23.1%) born from mothers with IgG seroconversion were diagnosed with cCMV. Neither IgM titers nor IgG titers differed significantly between cCMV and non-cCMV groups. The area under the ROC curve was 0.716 and the optimal cut-off for IgM was 7.28 index (sensitivity = 0.625, specificity = 0.965, positive predictive value = 0.238, negative predictive value = 0.993). Titers of IgG were not frequently elevated in pregnant women with positive IgM during the observation period, including in those with cCMV. All 11 cCMV cases were asymptomatic at birth and none had shown SNHL or developmental delay as of the last regular visit (mean age, 40 months).

Conclusions: Seroconversion of CMV IgG and high-titer IgM during early pregnancy are predictors of cCMV. High IgM titer (> 7.28 index) is a predictor despite relatively low sensitivity. Levels of IgG had already plateaued at first evaluation in mothers with cCMV. Maternal screening offered insufficient positive predictive value for diagnosing cCMV, but allowed identifying asymptomatic cCMV cases in an early stage.
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http://dx.doi.org/10.1186/s12884-019-2360-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585127PMC
June 2019

Critical role of Ca3.2 T-type calcium channels in the peripheral neuropathy induced by bortezomib, a proteasome-inhibiting chemotherapeutic agent, in mice.

Toxicology 2019 02 12;413:33-39. Epub 2018 Dec 12.

Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, 577-8802, Japan. Electronic address:

Bortezomib, a first-line agent for treatment of multiple myeloma, exhibits anticancer activity through proteasome inhibition. However, bortezomib-induced peripheral neuropathy (BIPN) is one of the most serious side effects. Since decreased proteasomal degradation of Ca3.2 T-type calcium channels in the primary afferents is involved in persistent pain, we investigated whether BIPN involves increased protein levels of Ca3.2 in mice. Six repeated i.p. administrations of bortezomib for 12 days developed persistent mechanical allodynia. Systemic administration of novel T-type calcium channel blockers, (2R/S)-6-prenylnaringenin and KTt-45, and of TTA-A2, the well-known blocker, reversed the BIPN. Ascorbic acid, known to block Ca3.2, but not Ca3.1 or 3.3, and silencing of Ca3.2 gene also suppressed BIPN. Protein levels of Ca3.2 in the dorsal root ganglion (DRG) at L4-L6 levels increased throughout days 1-21 after the onset of bortezomib treatment. Protein levels of USP5, a deubiquitinating enzyme that specifically inhibits proteasomal degradation of Ca3.2, increased in DRG on days 3-21, but not day 1, in bortezomib-treated mice. In DRG-derived ND7/23 cells, bortezomib increased protein levels of Ca3.2 and T-channel-dependent currents, as assessed by a patch-clamp method, but did not upregulate expression of Ca3.2 mRNA or USP5 protein. MG-132, another proteasome inhibitor, also increased Ca3.2 protein levels in the cultured cells. Given the previous evidence for USP5 induction following nociceptor excitation, our data suggest that BIPN involves the increased protein levels of Ca3.2 in nociceptors through inhibition of proteasomal degradation of Ca3.2 by bortezomib itself and then by USP5 that is upregulated probably in an activity-dependent manner.
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http://dx.doi.org/10.1016/j.tox.2018.12.003DOI Listing
February 2019

Design and synthesis of novel anti-hyperalgesic agents based on 6-prenylnaringenin as the T-type calcium channel blockers.

Bioorg Med Chem 2018 08 19;26(15):4410-4427. Epub 2018 Jul 19.

Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan; Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. Electronic address:

Since 6-prenylnaringenin (6-PNG) was recently identified as a novel T-type calcium channel blocker with the IC value around 1 µM, a series of flavanone derivatives were designed, synthesized and subsequently evaluated for T-channel-blocking activity in HEK293 cells transfected with Ca3.2 T-type channels using a patch-clamp technique. As a result, several new flavanones blocked Ca3.2-dependent T-currents more potently than 6-PNG. In the synthesized compounds, 6-(3-ethylpent-2-enyl)-5,7-dihydroxy-2-(2-hydroxyphenyl)chroman-4-one 8j, 6-(3-ethylpent-2-enyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 11b, 6-(2-cyclopentylideneethyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 11d, and 6-(2-Cyclopentylethyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 12c were more potent blocker than 6-PNG with the IC value of 0.39, 0.26, 0.46, and 0.50 µM, respectively. Among the above four derivatives, the compound 8j provided the best result in the in vivo experiments; i.e. systemic administration of 8j at the minimum dose completely restored neuropathic pain induced by partial sciatic nerve ligation in mice.
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http://dx.doi.org/10.1016/j.bmc.2018.07.023DOI Listing
August 2018

Blockade of T-type calcium channels by 6-prenylnaringenin, a hop component, alleviates neuropathic and visceral pain in mice.

Neuropharmacology 2018 08 18;138:232-244. Epub 2018 Jun 18.

Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan. Electronic address:

Since Ca3.2 T-type Ca channels (T-channels) expressed in the primary afferents and CNS contribute to intractable pain, we explored T-channel-blocking components in distinct herbal extracts using a whole-cell patch-clamp technique in HEK293 cells stably expressing Ca3.2 or Ca3.1, and purified and identified sophoraflavanone G (SG) as an active compound from SOPHORAE RADIX (SR). Interestingly, hop-derived SG analogues, (2S)-6-prenylnaringenin (6-PNG) and (2S)-8-PNG, but not naringenin, also blocked T-channels; IC (μM) of SG, (2S)-6-PNG and (2S)-8-PNG was 0.68-0.75 for Ca3.2 and 0.99-1.41 for Ca3.1. (2S)-6-PNG and (2S)-8-PNG, but not SG, exhibited reversible inhibition. The racemic (2R/S)-6-PNG as well as (2S)-6-PNG potently blocked Ca3.2, but exhibited minor effect on high-voltage-activated Ca channels and voltage-gated Na channels in differentiated NG108-15 cells. In mice, the mechanical allodynia following intraplantar (i.pl.) administration of an HS donor was abolished by oral or i.p. SR extract and by i.pl. SG, (2S)-6-PNG or (2S)-8-PNG, but not naringenin. Intraperitoneal (2R/S)-6-PNG strongly suppressed visceral pain and spinal ERK phosphorylation following intracolonic administration of an HS donor in mice. (2R/S)-6-PNG, administered i.pl. or i.p., suppressed the neuropathic allodynia induced by partial sciatic nerve ligation or oxaliplatin, an anti-cancer agent, in mice. (2R/S)-6-PNG had little or no effect on open-field behavior, motor performance or cardiovascular function in mice, and on the contractility of isolated rat aorta. (2R/S)-6-PNG, but not SG, was detectable in the brain after their i.p. administration in mice. Our data suggest that 6-PNG, a hop component, blocks T-channels, and alleviates neuropathic and visceral pain with little side effects.
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http://dx.doi.org/10.1016/j.neuropharm.2018.06.020DOI Listing
August 2018

Association of serum asymmetric dimethylarginine, homocysteine, and l-arginine concentrations during early pregnancy with hypertensive disorders of pregnancy.

Clin Chim Acta 2017 Dec 10;475:70-77. Epub 2017 Oct 10.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

Background: Our previous study suggested that a lower l-arginine level (<70μM) at early gestation is associated with pregnancy-induced hypertension. The maternal asymmetric dimethylarginine (ADMA) and homocysteine (Hcy) concentrations also have been reported to be increased in hypertensive disorders of pregnancy (HDP). These molecules have a key role in metabolism of nitric oxide. The aim of this study is to determine the most useful predictor of HDP at early gestation.

Methods: The concentrations of ADMA and Hcy at each of three periods in normal pregnancy were determined, and the values compared between the normal pregnancy and HDP groups. Moreover, the possible risk factors for the development of HDP also were evaluated using a multivariate logistic regression model and propensity score (PS).

Results: The maternal ADMA concentration was significantly elevated with advance of gestational age, while Hcy concentration was decreased from early to mid-gestation and increased from mid- to late-gestation in normal pregnancy. The maternal Hcy concentration at early gestation was significantly higher in the HDP group compared to that in the normal group. A higher maternal Hcy level (>7.2μM) in early pregnancy was independently associated with the development of HDP (PS-adjusted odds ratio=4.47, 95% confidence interval=1.51-12.82), as well as pre-pregnancy overweight [body mass index (BMI)>25kg/m], primipara status, and a lower maternal l-arginine level (<70μM).

Conclusions: The risk factors, such as overweight (BMI>25kg/m) before pregnancy, primipara status, higher Hcy (>7.2μM), and lower l-arginine (<70μM) concentration in early pregnancy, for development of HDP were detected.
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http://dx.doi.org/10.1016/j.cca.2017.10.007DOI Listing
December 2017

Gene expression of the concentration-sensitive sodium channel is suppressed in lipopolysaccharide-induced acute lung injury in mice.

Exp Lung Res 2017 04 30;43(3):150-157. Epub 2017 May 30.

a Department of Life Science, Faculty of Science and Engineering , Kindai University , Higashi-Osaka , Osaka , Japan.

Purpose: The concentration-sensitive sodium channel (Na) is expressed in alveolar type II epithelial cells and pulmonary microvascular endothelial cells in mouse lungs. We recently reported that Na contributes to amiloride-insensitive sodium transport in mouse lungs (Respiratory Physiology & Neurobiology, 2016). However, details regarding its physiological role in the lung remain unknown. To examine whether Na is involved in alveolar fluid clearance during an acute lung injury (ALI), we analyzed the relationship between Na gene expression in the lung and the development of pulmonary edema in lipopolysaccharide (LPS)-induced ALI mice.

Methods: LPS-induced ALI mice were prepared by the intratracheal administration of LPS. Bronchoalveolar lavage (BAL) neutrophils and lung water content (LWCs) were used as a marker of ALI and pulmonary edema, respectively. Na protein production in the lung was detected by immunoblotting and immunofluorescence. The gene expressions of Na and the epithelial sodium channel (ENaC) of LPS-induced ALI mice were examined by quantitative RT-PCR over a time course of 14 days.

Results: The BAL neutrophil count increased until day 2 after LPS administration and had nearly recovered by day 6. LWCs in LPS-induced mice gradually increased until day 8 and had recovered by day 14. The expression of the Na protein in the lungs of LPS-induced mice dramatically decreased from day 2 to day 6, but recovered by day 8. The mRNA expression of Na decreased in the lung, as well as those for α-, β-, and γ-ENaC during ALI. Thus, Na expression is suppressed during the development stage of pulmonary edema and then recovers in the convalescent phase.

Conclusion: Our results suggest that suppression of the gene expression of Na is involved in the development of pulmonary edema in ALI.
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http://dx.doi.org/10.1080/01902148.2017.1321064DOI Listing
April 2017

Sodium influx through cerebral sodium-glucose transporter type 1 exacerbates the development of cerebral ischemic neuronal damage.

Eur J Pharmacol 2017 Mar 4;799:103-110. Epub 2017 Feb 4.

Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan. Electronic address:

We recently reported that cerebral sodium-glucose transporter type 1 (SGLT-1) plays a role in exacerbation of cerebral ischemia. However, the mechanism by which cerebral SGLT-1 acts remains unclear. Here we demonstrated that sodium influx through cerebral SGLT-1 exacerbates cerebral ischemic neuronal damage. SGLT-specific sodium ion influx was induced using α-methyl-D-glucopyranoside (α-MG). Intracellular sodium concentrations in primary cortical neurons were estimated using sodium-binding benzofuran isophthalate fluorescence. SGLT-1 knockdown in primary cortical neurons and mice was achieved using SGLT-1 siRNA. The survival rates of primary cultured cortical neurons were assessed using biochemical assays 1 day after treatment. Middle cerebral artery occlusion (MCAO) was used to generate a focal cerebral ischemic model in SGLT-1 knockdown mice. The change in fasting blood glucose levels, infarction development, and behavioral abnormalities were assessed 1 day after MCAO. Treatment with 200mM α-MG induced a continuous increase in the intracellular sodium concentration, and this increase was normalized after α-MG removal. Neuronal SGLT-1 knockdown had no effect on 100µM HO-induced neuronal cell death; however, the knockdown prevented the neuronal cell death induced by 17.5mM glucose and the co-treatment of 100µM HO/8.75mM glucose. Neuronal SGLT-1 knockdown also suppressed the cell death induced by α-MG alone and the co-treatment of 100µM HO/0.01mM α-MG. Our in vivo results showed that the exacerbation of cerebral ischemic neuronal damage induced by the intracerebroventricular administration of 5.0µg α-MG/mouse was ameliorated in cerebral SGLT-1 knockdown mice. Thus, sodium influx through cerebral SGLT-1 may exacerbate cerebral ischemia-induced neuronal damage.
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http://dx.doi.org/10.1016/j.ejphar.2017.02.007DOI Listing
March 2017

High glucose induces N-linked glycosylation-mediated functional upregulation and overexpression of Ca3.2 T-type calcium channels in neuroendocrine-like differentiated human prostate cancer cells.

J Pharmacol Sci 2017 Jan 3;133(1):57-60. Epub 2017 Jan 3.

Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (Formerly Kinki University), Higashi-Osaka 577-8502, Japan. Electronic address:

Given that Ca3.2 T-type Ca channels were functionally regulated by asparagine (N)-linked glycosylation, we examined effects of high glucose on the function of Ca3.2, known to regulate secretory function, in neuroendocrine-like differentiated prostate cancer LNCaP cells. High glucose accelerated the increased channel function and overexpression of Ca3.2 during neuroendocrine differentiation, the former prevented by enzymatic inhibition of N-glycosylation and cleavage of N-glycans. Hyperglycemia thus appears to induce N-linked glycosylation-mediated functional upregulation and overexpression of Ca3.2 in neuroendocrine-like differentiated prostate cancer cells.
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http://dx.doi.org/10.1016/j.jphs.2016.12.004DOI Listing
January 2017

Establishment of a rat model of thrombosis induced by intravenous injection of anti-phosphatidylserine-prothrombin complex antibody.

Rheumatology (Oxford) 2017 06;56(6):1013-1018

Faculty of Health Sciences.

Objective: Recent studies have suggested that aPS-PT antibody is one of the most relevant autoantibodies to APS. This study aimed to demonstrate the pathogenicity of aPS-PT antibody in vivo .

Methods: At first, cultured rat vascular endothelial cells (RECs) were exposed to calf thymus-derived histones. Two hours later, lactate dehydrogenase release from the RECs and expression of PS on the cell surface were assessed. Next, we administered an i.v. injection of calf thymus-derived histones into Wistar rats (12.5 µg/g weight of 8-week-old female rats), and 2 h later they were given an i.v. injection of aPS-PT mAb (1.25 mg/g weight, n = 6) or an equal dose of rat IgM as controls (n = 5). Three days later, histological examination was conducted.

Results: Calf thymus-derived histones (>12.5 µg/ml) could injure RECs in vitro . Simultaneously, annexin V could bind to the RECs; thereby, this result indicated that cell-free histone exposure of vascular endothelial cells induced cell surface expression of PS, which is naturally present inside the plasma membrane. Thrombosis developed with higher frequency in the rats given an i.v. injection of aPS-PT mAb than in controls.

Conclusion: We established a rat model of thrombosis induced by i.v. injection of aPS-PT mAb.
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http://dx.doi.org/10.1093/rheumatology/kew477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445602PMC
June 2017

The organic mercury compounds, methylmercury and ethylmercury, inhibited ciliary movement of ventricular ependymal cells in the mouse brain around the concentrations reported for human poisoning.

Neurotoxicology 2016 12 13;57:69-74. Epub 2016 Sep 13.

Department of Life Science, Faculty of Science and Engineering, Kindai University, Higashi-Osaka, Japan. Electronic address:

Functions of the nervous system are supported by the flow of cerebrospinal fluid (CSF), which is driven by the ciliary beating of ventricular ependymal cells. The aim of the present study was to examine whether methylmercury (MeHg), a substance with potent neurotoxicity in humans, affects the ciliary movement. The effects of another organic mercury compound, ethylmercury (EtHg), were also assessed for comparison. Toxicity of MeHg or EtHg was evaluated by measuring alterations in the ciliary beat frequency of ependymal cells lining the third ventricle of mouse brain slices. The obtained results were: (1) Both MeHg and EtHg started to inhibit ciliary motility between 1 and 3μM, the reported threshold limit of MeHg in humans. (2) An abrupt increase was observed in the inhibitory curves from 3 to 6μM for MeHg and EtHg. (3) The "give-in" concentration, i.e., concentration at which the cilia lose the ability to recover, for MeHg and EtHg was 6μM and 12μM, respectively. (4) Ciliary beating was irreversibly halted by MeHg and EtHg at concentrations above 12μM and 30μM, respectively. (5) The estimated half-maximal inhibitory concentration (IC) for MeHg and EtHg was 5.53μM and 5.80μM, respectively. Based on these findings, we conclude that: (a) Ependymal cell cilia movement in mice was inhibited by MeHg in a concentration-dependent manner around concentrations reported to cause poisoning in humans; EtHg inhibited ciliary motility to a less extent. (b) Inhibition of CSF flow by suppression of ciliary movement is suggested to be an additional route for MeHg poisoning in humans, especially in prenatal exposure than in adult exposure.
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http://dx.doi.org/10.1016/j.neuro.2016.08.007DOI Listing
December 2016

Semiautomated Segmentation and Measurement of Cytoplasmic Vacuoles in a Neutrophil With General-Purpose Image Analysis Software.

J Clin Lab Anal 2016 Nov 7;30(6):918-923. Epub 2016 Apr 7.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

Background: Morphological observation of blood or marrow film is still described nonquantitatively. We developed a semiautomatic method for segmenting vacuoles from the cytoplasm using Photoshop (PS) and Image-J (IJ), called PS-IJ, and measured the relative entire cell area (rECA) and relative areas of vacuoles (rAV) in the cytoplasm of neutrophil with PS-IJ.

Methods: Whole-blood samples were stored at 4°C with ethylenediaminetetraacetate and in two different preserving manners (P1 and P2). Color-tone intensity levels of neutrophil images were semiautomatically compensated using PS, and then vacuole portions were automatically segmented by IJ. The rAV and rECA were measured by counting pixels by IJ. For evaluating the accuracy in segmentations of vacuoles with PS-IJ, the rAV/rECA ratios calculated with results from PS-IJ were compared with those calculated with human eye and IJ (HE-IJ).

Results: The rECA and rAV/ in P1 significantly (P < 0.05, P < 0.05) were enlarged and increased, but did not significantly (P = 0.46, P = 0.21) change in P2. The rAV/rECA ratios by PS-IJ were significantly correlated (r = 0.90, P < 0.01) with those by HE-IJ.

Conclusion: PS-IJ method can successfully segment vacuoles and measure the rAV and rECA, becoming a useful tool for quantitative description of morphological observation of blood and marrow film.
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http://dx.doi.org/10.1002/jcla.21957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6807187PMC
November 2016

Hypersensitivity Events, Including Potentially Hypersensitivity-Related Skin Events, with Dapagliflozin in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis.

Clin Drug Investig 2016 Nov;36(11):925-933

AstraZeneca Gothenburg, Patient Safety, Pepparredsleden 1, 43150, Mölndal, Sweden.

Background: In patients with type 2 diabetes mellitus (T2DM), dapagliflozin improves glycemic control and has a safety profile typically related to its mechanism of action. Hypersensitivity adverse events (AEs) have been reported in some patients with sodium-glucose cotransporter 2 (SGLT2) inhibitors, including a recent report of dermatological AEs in Japan.

Methods: We investigated the frequency and characteristics of hypersensitivity AEs, including potentially hypersensitivity-related skin AEs, across 21 phase IIb/III trials of dapagliflozin (N = 5936) versus active or placebo comparators (N = 3403), including the subpopulation of Asian patients (N = 1563).

Results: Overall, AEs and serious AEs (SAEs) of hypersensitivity were infrequent and were reported in a similar proportion of patients with dapagliflozin versus active or placebo comparators (AEs: 4.5 vs. 4.3 %; SAEs: 0.2 vs. 0.1 %, respectively). The most common events affected the skin or subcutaneous tissue: rash (dapagliflozin: 1.1 %, comparator: 1.1 %), eczema (0.6, 0.8 %), dermatitis (0.5, 0.4 %), and urticaria (0.5, 0.2 %). Few patients discontinued as a result of hypersensitivity AEs (≤0.2 %). In patients of Asian descent, a lower frequency of hypersensitivity AEs was observed with dapagliflozin versus comparators (2.0 vs. 4.5 %). In the subset of placebo-controlled trials, hypersensitivity AEs were slightly more frequent with dapagliflozin than with placebo across the overall population (4.7 vs. 3.8 %), and less frequent with dapagliflozin in Asian patients (1.5 vs. 5.0 %).

Conclusions: The findings of this post hoc analysis indicate that dapagliflozin does not lead to an increased risk of serious hypersensitivity reactions or potentially hypersensitivity-related skin events among patients with T2DM, including Asian patients. Long-term outcome studies and postmarketing surveillance will provide further information on hypersensitivity reactions with SGLT2 inhibitors. CLINICALTRIALS.

Gov Identifiers: NCT01042977, NCT01031680, NCT00855166, NCT00984867, NCT01294423, NCT00673231, NCT00972244, NCT00680745, NCT00660907, NCT01095653, NCT00831779, NCT00976495, NCT00859898, NCT00736879, NCT00683878, NCT00663260, NCT00643851, NCT00528879, NCT00528372, NCT00357370, NCT00263276.
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http://dx.doi.org/10.1007/s40261-016-0438-3DOI Listing
November 2016

Contribution of concentration-sensitive sodium channels to the absorption of alveolar fluid in mice.

Respir Physiol Neurobiol 2016 09 1;231:45-54. Epub 2016 Jun 1.

Department of Life Science, School of Science and Engineering, Kindai University, Higashi-Osaka, Osaka, Japan. Electronic address:

The concentration-sensitive sodium channel (Nac) is activated by an increase in the extracellular sodium concentration. Although the expression of Nac in alveolar type II epithelial cells (AEC II) has been reported previously, the physiological role of Nac in the lung has not been established. We characterized Nac expression and examined amiloride-insensitive sodium transport mediated by Nac in mouse lung. Immunofluorescence studies revealed that Nac did not colocalize with either aquaporin 5 or cystic fibrosis transmembrane conductance regulator, but partially colocalized with the epithelial sodium channel γ-subunit. Immunoelectron microscopy studies showed that Nac localized at the basolateral membrane of pulmonary microvascular endothelial cells (PMVECs). Nac mRNA and protein were expressed in PMVECs isolated from the lungs of mice. Image analysis indicated that sodium influx into the alveolar wall was dependent on increases in extracellular sodium concentration. We conclude that Nac expressed in PMVECs and AEC II contributes to the reabsorption of sodium via an amiloride-insensitive pathway during alveolar fluid clearance.
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http://dx.doi.org/10.1016/j.resp.2016.05.017DOI Listing
September 2016

Sodium transport through the cerebral sodium-glucose transporter exacerbates neuron damage during cerebral ischaemia.

J Pharm Pharmacol 2016 Jul 3;68(7):922-31. Epub 2016 May 3.

Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan.

Objectives: We recently demonstrated that the cerebral sodium-glucose transporter (SGLT) is involved in postischaemic hyperglycaemia-induced exacerbation of cerebral ischaemia. However, the associated SGLT-mediated mechanisms remain unclear. Thus, we examined the involvement of cerebral SGLT-induced excessive sodium ion influx in the development of cerebral ischaemic neuronal damage.

Methods: [Na+]i was estimated according to sodium-binding benzofuran isophthalate fluorescence. In the in vitro study, primary cortical neurons were prepared from fetuses of ddY mice. Primary cortical neurons were cultured for 5 days before each treatment with reagents, and these survival rates were assessed using biochemical assays. In in vivo study, a mouse model of focal ischaemia was generated using middle cerebral artery occlusion (MCAO).

Key Findings: In these experiments, treatment with high concentrations of glucose induced increment in [Na+]i, and this phenomenon was suppressed by the SGLT-specific inhibitor phlorizin. SGLT-specific sodium ion influx was induced using a-methyl-D-glucopyranoside (a-MG) treatments, which led to significant concentration-dependent declines in neuronal survival rates and exacerbated hydrogen peroxide-induced neuronal cell death. Moreover, phlorizin ameliorated these effects. Finally, intracerebroventricular administration of a-MG exacerbated the development of neuronal damage induced by MCAO, and these effects were ameliorated by the administration of phlorizin.

Conclusions: Hence, excessive influx of sodium ions into neuronal cells through cerebral SGLT may exacerbate the development of cerebral ischaemic neuronal damage.
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http://dx.doi.org/10.1111/jphp.12571DOI Listing
July 2016

The prostaglandin E2/EP4 receptor/cyclic AMP/T-type Ca(2+) channel pathway mediates neuritogenesis in sensory neuron-like ND7/23 cells.

J Pharmacol Sci 2016 Mar 27;130(3):177-80. Epub 2016 Feb 27.

Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, (formerly Kinki University), Higashi-Osaka 577-8502, Japan. Electronic address:

We investigated mechanisms for the neuritogenesis caused by prostaglandin E2 (PGE2) or intracellular cyclic AMP (cAMP) in sensory neuron-like ND7/23 cells. PGE2 caused neuritogenesis, an effect abolished by an EP4 receptor antagonist or inhibitors of adenylyl cyclase (AC) or protein kinase A (PKA) and mimicked by the AC activator forskolin, dibutyryl cAMP (db-cAMP), and selective activators of PKA or Epac. ND7/23 cells expressed both Cav3.1 and Cav3.2 T-type Ca(2+) channels (T-channels). The neuritogenesis induced by db-cAMP or PGE2 was abolished by T-channel blockers. T-channels were functionally upregulated by db-cAMP. The PGE2/EP4/cAMP/T-channel pathway thus appears to mediate neuritogenesis in sensory neurons.
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http://dx.doi.org/10.1016/j.jphs.2016.02.008DOI Listing
March 2016

Therapeutic potential of RQ-00311651, a novel T-type Ca2+ channel blocker, in distinct rodent models for neuropathic and visceral pain.

Pain 2016 08;157(8):1655-1665

Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.

T-type Ca channels (T channels), particularly Cav3.2 among the 3 isoforms, play a role in neuropathic and visceral pain. We thus characterized the effects of RQ-00311651 (RQ), a novel T-channel blocker, in HEK293 cells transfected with human Cav3.1 or Cav3.2 by electrophysiological and fluorescent Ca signaling assays, and also evaluated the antiallodynic/antihyperalgesic activity of RQ in somatic, visceral, and neuropathic pain models in rodents. RQ-00311651 strongly suppressed T currents when tested at holding potentials of -65 ∼ -60 mV, but not -80 mV, in the Cav3.1- or Cav3.2-expressing cells. RQ-00311651 also inhibited high K-induced Ca signaling in those cells. In mice, RQ, administered intraperitoneally (i.p.) at 5 to 20 mg/kg or orally at 20 to 40 mg/kg, significantly suppressed the somatic hyperalgesia and visceral pain-like nociceptive behavior/referred hyperalgesia caused by intraplantar and intracolonic administration of NaHS or Na2S, H2S donors, respectively, which involve the enhanced activity of Cav3.2 channels. RQ-00311651, given i.p. at 5 to 20 mg/kg, exhibited antiallodynic or antihyperalgesic activity in rats with spinal nerve injury-induced neuropathy or in rats and mice with paclitaxel-induced neuropathy. Oral and i.p. RQ at 10 to 20 mg/kg also suppressed the visceral nociceptive behavior and/or referred hyperalgesia accompanying cerulein-induced acute pancreatitis and cyclophosphamide-induced cystitis in mice. The analgesic and antihyperalgesic/antiallodynic doses of oral and i.p. RQ did not significantly affect the locomotor activity and motor coordination. Together, RQ is considered a state-dependent blocker of Cav3.1/Cav3.2 T channels and may serve as an orally available analgesic for treatment of neuropathic and inflammatory pain including distinct visceral pain with minimum central side effects.
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http://dx.doi.org/10.1097/j.pain.0000000000000565DOI Listing
August 2016

Functional upregulation of the H2S/Cav3.2 channel pathway accelerates secretory function in neuroendocrine-differentiated human prostate cancer cells.

Biochem Pharmacol 2015 Oct 7;97(3):300-9. Epub 2015 Aug 7.

Division of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan. Electronic address:

Neuroendocrine-differentiated prostate cancer cells may contribute to androgen-independent proliferation of surrounding cells through Ca(2+)-dependent secretion of mitogenic factors. Human prostate cancer LNCaP cells, when neuroendocrine-differentiated, overexpress Cav3.2 T-type Ca(2+) channels that contribute to Ca(2+)-dependent secretion. Given evidence for the acceleration of Cav3.2 activity by hydrogen sulfide (H2S), we examined the roles of the H2S/Cav3.2 pathway and then analyzed the molecular mechanisms of the Cav3.2 overexpression in neuroendocrine-differentiated LNCaP cells. LNCaP cells were differentiated by dibutyryl cyclic AMP. Protein levels and T-type Ca(2+) channel-dependent currents (T-currents) were measured by immunoblotting and whole-cell pacth-clamp technique, respectively. Spontaneous release of prostatic acid phosphatase (PAP) was monitored to evaluate secretory function. The differentiated LNCaP cells exhibited neurite outgrowth, androgen-independent proliferation and upregulation of mitogenic factors, and also showed elevation of Cav3.2 expression or T-currents. Expression of cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), H2S-forming enzymes, and spontaneous secretion of PAP increased following the differentiation. The augmented T-currents were enhanced by H2S donors and suppressed by inhibitors of CSE, but not CBS. The PAP secretion was reduced by inhibition of CSE or T-type Ca(2+) channels. During differentiation, Egr-1 and REST, positive and negative transcriptional regulators for Cav3.2, were upregulated and downregulated, respectively, and Egr-1 knockdown prevented the Cav3.2 overexpression. Our data suggest that, in neuroendocrine-differentiated LNCaP cells, H2S formed by the upregulated CSE promotes the activity of the upregulated Cav3.2, leading to the elevated secretory functions. The overexpression of Cav3.2 appears to involve upregulation of Egr-1 and downregulation of REST.
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http://dx.doi.org/10.1016/j.bcp.2015.08.005DOI Listing
October 2015

Is the serum l-arginine level during early pregnancy a predictor of pregnancy-induced hypertension?

J Clin Biochem Nutr 2015 Jul 4;57(1):74-81. Epub 2015 Jun 4.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

The objective of this study was to determine the concentration of serum l-arginine in healthy pregnant women and infant cord blood and to compare them with those in patients with pregnancy-induced hypertension (PIH). The serum concentration of l-arginine in normal pregnant women at early gestation (n = 186) was determined and analyzed based on maternal factors such as the age, pre-pregnancy body mass index (BMI), smoking and alcohol habits before pregnancy. Similarly, the concentration of cord blood of the newborns (n = 142) was also analyzed. These values were compared with those in the PIH group (n = 21). The potential risk factors for PIH were also estimated. The serum concentration of l-arginine at early gestation in normal pregnant women (88.65 ± 19.96 µM) was not affected by the maternal age and BMI before pregnancy. A lower l-arginine concentration at early gestation (<70 µM) significantly elevated PIH risk [adjusted odds ratio (OR) = 4.26, 95% CI 1.29-14.50]. In addition, either women with large body mass before pregnancy (BMI>25 kg/m(2)) or primipara women also showed a significant association with PIH risk [adjusted OR = 10.55 (2.95-40.68); 5.25 (1.72-19.15), respectively]. In conclusion, a lower l-arginine concentration at early gestation, overweight before pregnancy (BMI>25 kg/m(2)) and primipara could predict to the development of PIH.
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http://dx.doi.org/10.3164/jcbn.14-104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512889PMC
July 2015

Japanese external quality assessment program to standardize HIV-1 drug-resistance testing (JEQS2010 program) using in vitro transcribed RNA as reference material.

AIDS Res Hum Retroviruses 2015 Mar 3;31(3):318-25. Epub 2014 Dec 3.

1 Faculty of Health Sciences, Hokkaido University , Sapporo, Japan .

To design appropriate antiretroviral therapy regimens and avoid the emergence of human immunodeficiency virus (HIV)-1 variants with reduced susceptibility to antiretroviral drugs, genotypic drug-resistance testing (HIV genotyping) is strongly recommended. To monitor the quality of HIV genotyping in Japan, we performed an external quality assessment (EQA), named the Japanese external quality assessment program, to standardize HIV genotyping (JEQS). To accurately evaluate the quality of HIV genotyping, we employed as reference material (RM) a well-characterized sample, in vitro transcribed RNA (trRNA) that includes the HIV gag-pol sequence, and created a JEQS2010 panel consisting of three single variant and three mixed trRNA samples. All 11 participating laboratories showed high concordance rates (>96%) for the single variant samples. Eight laboratories also showed good rates of detecting minor variants, but three laboratories failed to detect the variants comprising one-half of the sample. These three laboratories used a common primer that had four internal mismatches to the minor trRNA clone. This program showed the usefulness of trRNA as RM, the high quality of HIV genotyping, and extensive interlaboratory variation in the ability to detect minor variants. These results suggest that improving the quality of HIV genotyping in Japan requires regularly implementing the EQA program and improving the HIV genotyping protocol in each laboratory.
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http://dx.doi.org/10.1089/aid.2014.0059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347889PMC
March 2015
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