Takahiko Nagamine, Takeshi Watanabe and Akira Toyofuku : QTc Shortening on Electrocardiogram With Amitriptyline May Indicate No Effect on Pain Relief in Burning Mouth Syndrome., Clinical Neuropharmacology, 2024.
(Summary)
Amitriptyline provides analgesia in about half of BMS patients, but some BMS patients have worse pain with amitriptyline. Not only do changes in the QTc detect amitriptyline adverse effects with prolongation, but also, conversely, its shortening predicts amitriptyline ineffectiveness.
Satomi Tomida, Teruhide Koyama, Etsuko Ozaki, Naoyuki Takashima, Midori Morita, Koichi Sakaguchi, Yasuto Naoi, Yuichiro Nishida, Megumi Hara, Asahi Hishida, Takashi Tamura, Rieko Okada, Yoko Kubo, Jun Otonari, Hiroaki Ikezaki, Yohko Nakamura, Miho Kusakabe, Shiroh Tanoue, Chihaya Koriyama, N Yuriko Koyanagi, Hidemi Ito, Sadao Suzuki, Takahiro Otani, Naoko Miyagawa, Yukiko Okami, Kokichi Arisawa, Takeshi Watanabe, Kiyonori Kuriki, Kenji Wakai and Keitaro Matsuo : Seven-plus hours of daily sedentary time and the subsequent risk of breast cancer: Japan Multi-Institutional Collaborative Cohort Study., Cancer Science, 2023.
(Summary)
This study aimed to investigate the association between daily sedentary time and the risk of breast cancer (BC) in a large Japanese population. The participants were 36,023 women aged 35-69years from the Japan Multi-Institutional Collaborative Cohort Study. Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for BC incidence in relation to time spent sedentarily (categorical variables: <7 and 7hours/day [h/d]). Additionally, the associations of BC incidence to the joint effect of sedentary time with each component of physical activity, such as leisure-time metabolic equivalents (METs), frequency of leisure-time physical activity, and daily walking time, were examined. During 315,189 person-years of follow-up, 554 incident cases of BC were identified. When compared to participants who spent <7h/d sedentary, those who spent 7h/d sedentary have a significantly higher risk of BC (HR, 1.36; 95% CI, 1.07-1.71). The corresponding HRs among participants who spent 7h/d sedentary with more physical activity, such as 1h/d for leisure-time METs, 3days/week of leisure-time physical activity, and 1h/d of daily walking were 1.58 (95% CI, 1.11-2.25), 1.77 (95% CI, 1.20-2.61), and 1.42 (95% CI, 1.10-1.83), respectively, compared with those who spent <7h/d sedentary. This study found that spending 7h/d of sedentary time is associated with the risk of BC. Neither leisure-time physical activity nor walking had a BC-preventive effect in those with 7h/d of sedentary time.
Daisaku Nishimoto, Rie Ibusuki, Ippei Shimoshikiryo, Kenichi Shibuya, Shiroh Tanoue, Chihaya Koriyama, Toshiro Takezaki, Isao Oze, Hidemi Ito, Asahi Hishida, Takashi Tamura, Yasufumi Kato, Yudai Tamada, Yuichiro Nishida, Chisato Shimanoe, Sadao Suzuki, Takeshi Nishiyama, Etsuko Ozaki, Satomi Tomida, Kiyonori Kuriki, Naoko Miyagawa, Keiko Kondo, Kokichi Arisawa, Takeshi Watanabe, Hiroaki Ikezaki, Jun Otonari, Kenji Wakai and Keitaro Matsuo : Association between awareness of limiting food intake and all-cause mortality: A cohort study in Japan, Journal of Epidemiology, 2023.
(Summary)
Improving diets requires an awareness of the need to limit foods for which excessive consumption is a health problem. Since there are limited reports on the link between this awareness and mortality risk, we examined the association between awareness of limiting food intake (energy, fat, and sweets) and all-cause mortality in a Japanese cohort study. Participants comprised 58,772 residents (27,294 men; 31,478 women) aged 35-69 years who completed baseline surveys of the Japan Multi-Institutional Collaborative Cohort Study from 2004 to 2014. Hazard ratios (HRs) for all-cause mortality and 95% confidence intervals (CIs) were estimated by sex using a Cox proportional hazard model, with adjustment for related factors. Mediation analysis with fat intake as a mediator was also conducted. The mean follow-up period was 11 years and 2,516 people died. Estimated energy and fat intakes according to the Food Frequency Questionnaire were lower in those with awareness of limiting food intake than in those without this awareness. Women with awareness of limiting fat intake showed a significant decrease in mortality risk (HR=0.73; 95% CI, 0.55 to 0.94). Mediation analysis revealed that this association was due to the direct effect of the awareness of limiting fat intake and that the total effect was not mediated by actual fat intake. Awareness of limiting energy or sweets intake was not related to mortality risk reduction. Awareness of limiting food intake had a limited effect on reducing all-cause mortality risk.
Tamura Takashi, Wakai Kenji, Kato Yasufumi, Tamada Yudai, Kubo Yoko, Okada Rieko, Nagayoshi Mako, Hishida Asahi, Imaeda Nahomi, Goto Chiho, Ikezaki Hiroaki, Otonari Jun, Hara Megumi, Tanaka Keitaro, Nakamura Yohko, Kusakabe Miho, Ibusuki Rie, Koriyama Chihaya, Oze Isao, Ito Hidemi, Suzuki Sadao, Nakagawa-Senda Hiroko, Ozaki Etsuko, Matsui Daisuke, Kuriki Kiyonori, Kondo Keiko, Takashima Naoyuki, Takeshi Watanabe, Sakurako Kamano and Matsuo Keitaro : Dietary carbohydrate and fat intakes and risk of mortality in the Japanese population: the Japan Multi-Institutional Collaborative Cohort Study., The Journal of Nutrition, 2023.
(Summary)
An unfavorable association with mortality was observed for low carbohydrate intake in men and for high carbohydrate intake in women. High fat intake could be associated with a lower mortality risk in women among Japanese adults with a relatively high carbohydrate intake.
Takeshi Watanabe, Mette Sieg, Sigrid Juhl Lunde, Mads Persson, Pankaj Taneja, Lene Baad-Hansen, Maria Pigg and Lene Vase : Nocebo response in dentistry: A systematic review and meta-analysis of adverse events in analgesic trials of third molar removal, Journal of Oral Rehabilitation, Vol.50, No.4, 332-342, 2023.
(Summary)
The nocebo response refers to the phenomenon where non-specific factors, including negative verbal suggestion and treatment expectations, cause adverse events (AE) following a placebo treatment. Non-specific factors are also likely to influence AE occurrence following administration of active pharmacological treatments. This meta-analysis aimed to estimate the nocebo response in dentistry by assessing the AEs prevalence in placebo- and active arms of randomised controlled trials (RCTs) assessing analgesic treatment following third molar (M3) surgery. A systematic search was performed in PubMed, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials. Eligible studies had to report the number of patients experiencing at least one drug-related AE (patients with AE ≥ 1) separately for the active and placebo arms. The proportion of patients with AE ≥ 1 and drug-related dropouts were pooled, and risk differences (RDs) between patients in the placebo- and active arm were calculated. In 50 independent RCTs of 47 identified articles, the pooled rates of patients with AE ≥ 1 were 22.8% in the placebo arm and 20.6% in the active arm. The pooled rates of drug-related dropout were 0.24% in the placebo arm and 0.08% in the active arm. There were no significant RDs in patients with AE ≥ 1 and drug-related dropouts. These results show that patients in the placebo arm reported AEs to the same extent as patients receiving active treatment, suggesting that most AEs in analgesic medication following M3 surgery may be attributed to the nocebo phenomenon.
(Keyword)
Nocebo effect / Surgery, Oral / Analgesics [Pharmacological Action] / Pain / Long Term Adverse Effects / Molar, Third
Takeshi Watanabe, Kokichi Arisawa, Tien Van Nguyen, Masashi Ishizu, Sakurako Katsuura-Kamano, Asahi Hishida, Takashi Tamura, Yasufumi Kato, Rieko Okada, Rie Ibusuki, Chihaya Koriyama, Sadao Suzuki, Takahiro Otani, Teruhide Koyama, Satomi Tomida, Kiyonori Kuriki, Naoyuki Takashima, Naoko Miyagawa, Kenji Wakai and Keitaro Matsuo : Coffee and Metabolic Phenotypes: A Cross-sectional Analysis of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study, Nutrition, Metabolism, and Cardiovascular Diseases : NMCD, Vol.33, No.3, 620-630, 2023.
(Summary)
To date, the relationship between coffee consumption and metabolic phenotypes has hardly been investigated and remains controversial. Therefore, the aim of this cross-sectional study is to examine the associations between coffee consumption and metabolic phenotypes in a Japanese population. We analyzed the data of 26,363 subjects (aged 35-69 years) in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Coffee consumption was assessed using a questionnaire. Metabolic Syndrome (MetS) was defined according to the Joint Interim Statement Criteria of 2009, using body mass index (BMI) instead of waist circumference. Subjects stratified by the presence or absence of obesity (normal weight: BMI <25 kg/m; obesity: BMI ≥25 kg/m) were classified by the number of MetS components (metabolically healthy: no components; metabolically unhealthy: one or more components) other than BMI. In multiple logistic regression analyses adjusted for sex, age, and other potential confounders, high coffee consumption (≥3 cups/day) was associated with a lower prevalence of MetS and metabolically unhealthy phenotypes both in normal weight (OR 0.83, 95% CI 0.76-0.90) and obese subjects (OR 0.83, 95% CI 0.69-0.99). Filtered/instant coffee consumption was inversely associated with the prevalence of MetS and metabolically unhealthy phenotypes, whereas canned/bottled/packed coffee consumption was not. The present results suggest that high coffee consumption, particularly filtered/instant coffee, is inversely associated with the prevalence of metabolically unhealthy phenotypes in both normal weight and obese Japanese adults.
(Keyword)
Humans / Cross-Sectional Studies / Coffee / Cohort Studies / Japan / Metabolic Syndrome / Obesity / Body Mass Index / Phenotype / Risk Factors
Takuya Sakashita, Yasuyuki Nakamura, Yoichi Sutoh, Atsushi Shimizu, Tsuyoshi Hachiya, Yayoi Otsuka-Yamasaki, Naoyuki Takashima, Aya Kadota, Katsuyuki Miura, Yoshikuni Kita, Hiroaki Ikezaki, Jun Otonari, Keitaro Tanaka, Chisato Shimanoe, Teruhide Koyama, Isao Watanabe, Sadao Suzuki, Hiroko Nakagawa-Senda, Asahi Hishida, Takashi Tamura, Yasufumi Kato, Rieko Okada, Kiyonori Kuriki, Sakurako Katsuura-Kamano, Takeshi Watanabe, Shiroh Tanoue, Chihaya Koriyama, Isao Oze, Yuriko N. Koyanagi, Yohko Nakamura, Miho Kusakabe, Masahiro Nakatochi, Yukihide Momozawa, Kenji Wakai and Keitaro Matsuo : Comparison of the loci associated with HbA1c and blood glucose levels identified by a genome-wide association study in the Japanese population, Diabetology International, Vol.14, No.2, 188-198, 2023.
(Summary)
Hemoglobin A1c (HbA1c) levels are widely employed to diagnose diabetes. However, estimates of the heritability of HbA1c and glucose levels are different. Therefore, we explored HbA1c- and blood glucose-associated loci in a non-diabetic Japanese population. We conducted a two-stage genome-wide association study (GWAS) on variants associated with HbA1c and blood glucose levels in a Japanese population. In the initial stage, data of 4911 participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) were subjected to discovery analysis. In the second stage, two datasets from the Tohoku Medical Megabank project, with 8175 and 40,519 participants, were used for the replication study. Association of the imputed variants with HbA1c and blood glucose levels was determined via linear regression analyses adjusted for age, sex, body mass index (BMI), smoking, and genetic principal components (PC1-PC10). Moreover, we performed a BMI-stratified GWAS on HbA1c levels in the J-MICC. The discovery analysis and BMI-stratified GWAS results were validated with re-analyses of normalized HbA1c levels adjusted for site in addition to the above, and blood glucose adjusted for fasting time as an additional covariate. Genetic variants associated with HbA1c levels were identified in and . None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m and BMI < 25 kg/m. The variant rs2299620 in might affect HbA1c levels differentially based on BMI grouping in the Japanese population. The online version contains supplementary material available at 10.1007/s13340-023-00618-0.
Toru Inoue, Takeshi Watanabe and Kayo Ishikawa : Evaluation of Geriatric Nutritional Risk Index, Serum Albumin, Body Mass Index, and related factors of these three indexes in the elderly staying in nursing homes, Shikoku Acta Medica, Vol.78, No.3, 4, 95-102, 2022.
(Summary)
Geriatric Nutritional Risk Index(GNRI)is a nutritional risk assessment tool for the elderly calculated from Body Mass Index(BMI)and serum albumin level. GNRI score has been known to be correlated with Mini nutritional assessment score and be calculated easily, therefore this index has been utilized as a useful tool to evaluate nutritional status of the elderly staying in nursing homes. The aim of this study is to investigate the relationship between GNRI and indicators of geriatric health status such as activities of daily living(ADL), cognitive functions, oral functions and number of regular drugs. This cross-sectional study was conducted with the data of 207(40 males, 167 females)nursing home residents examined in 2019 - 2020. We evaluated GNRI, serum albumin level, BMI, ADL, HDS-R, oral functions, number of regular drugs, and CBC(complete blood count). Multiple regression analysis was performed by using the obtained data. As a result, GNRI was associated with ADL and HDS-R. BMI and serum albumin, which are components of GNRI, were associated with ADL and HDS-R, respectively. This study suggests that that GNRI is associated with mobility and cognitive functions. Therefore, GNRI could be a useful assessment tool for overall health status of the elderly, not just their nutritional status.
(Keyword)
nursing homes / nutrition / activities of daily living / cognitive functions
Takeshi Watanabe, Mette Sieg, Sigrid Juhl Lunde, Pankaj Taneja, Lene Baad-Hansen, Maria Pigg and Lene Vase : What is the nocebo effect and does it apply to dentistry? A narrative review., Journal of Oral Rehabilitation, 2022.
(Summary)
Evidence for the nocebo effect, a phenomenon characterised by suboptimal treatment efficacy, worsening of symptoms, or the occurrence of adverse events caused by an individual's negative treatment expectations, is growing across a multitude of medical fields. Within dentistry, little attention has been paid to patients' negative expectations, despite a number of studies supporting the influence of related factors, such as dental fear and anxiety, on the severity of peri- and post-operative dental pain. Only recently, a small number of commentaries and letters have emerged, urging dentists to recognise the possible existence of nocebo effects in dentistry and its implications for patient care. The present review summarises essential evidence of the nocebo phenomenon especially in relation to pain and drug administration. Subsequently, an overview of the current evidence of the nocebo phenomenon in the dental field is presented. Finally, based on the general knowledge of the nocebo effect, the review indicates fruitful arrays of research into the nocebo effect in dentistry.
Yojiro Umezaki, Motoko Watanabe, Yukiko Shinohara, Shiori Sugawara, Kaoru Kawasaki, Trang T.H. Tu, Takeshi Watanabe, Takayuki Suga, Anna Miura, Miho Takenoshita, Yusuke Sato, Ichiro Minami, Jun Oyama, Akira Toriihara, Tatsuya Yoshikawa, Toru Naito, Haruhiko Motomura and Akira Toyofuku : Comparison of Cerebral Blood Flow Patterns in Patients with Phantom Bite Syndrome with Their Corresponding Clinical Features., Neuropsychiatric Disease and Treatment, Vol.16, 2277-2284, 2020.
(Summary)
Patients with PBS showed blood flow imbalance in the thalamus and parietal region corresponding to symptom laterality. There are two types of symmetrical and asymmetrical rCBF patterns in the pathophysiology of PBS despite similar clinical manifestations.
Kaoru Kawasaki, Shiori Sugawara, Kazuya Watanabe, Chaoli Hong, Trang T.H. Tu, Takeshi Watanabe, Junichiro Sakamoto, Norio Yoshino, Takayuki Suga, Lou Mikuzuki, Miho Takenoshita, Satoshi Takada, Tohru Kurabayashi and Akira Toyofuku : Differences in the Clinical Characteristics of Persistent Idiopathic Facial Pain (Atypical Odontalgia) Patients with or Without Neurovascular Compression of the Trigeminal Nerve., Pain Medicine, Vol.21, No.4, 814-821, 2020.
(Summary)
These results suggest that PIFP patients can be divided into two groups: one consistent with a neuropathic pain phenotype when NVC is present and a functional somatic symptom phenotype when presenting without NVC. Our findings may enable a more precise understanding of pathophysiology of PIFP and lead to better treatment strategies.
Yukiko Shinohara, Yojiro Umezaki, Ichiro Minami, Motoko Watanabe, Anna Miura, Lou Mikutsuki, Kaoru Kawasaki, Shiori Sugawara, Trang T.H. Tu, Takayuki Suga, Takeshi Watanabe, Tatsuya Yoshikawa, Miho Takenoshita, Haruhiko Motomura and Akira Toyofuku : Comorbid depressive disorders and left-side dominant occlusal discomfort in patients with phantom bite syndrome., Journal of Oral Rehabilitation, Vol.47, No.1, 36-41, 2019.
(Summary)
The distributions of the side with symptoms of PBS were different between those with and without comorbid psychiatric disorders, suggesting that psychiatric disorders might affect occlusal sensation due to a subtle dysfunction in brain areas central to sensory integration. Central dysfunction might play an important role in PBS.
Trang T.H. Tu, Anna Miura, Yukiko Shinohara, Lou Mikuzuki, Kaoru Kawasaki, Shiori Sugawara, Takayuki Suga, Takeshi Watanabe, Yuma Aota, Yojiro Umezaki, Miho Takenoshita and Akira Toyofuku : Pharmacotherapeutic outcomes in atypical odontalgia: determinants of pain relief., Journal of Pain Research, Vol.12, 831-839, 2019.
(Summary)
Our findings confirm the efficacy of tricyclic antidepressants (TCAs) as a treatment for AO and indicate that other medications, especially aripiprazole used in combination with a TCA, may be useful. A considerable number of patients, especially women, those with lower levels of depression at baseline, and those who responded to 4 weeks of treatment, achieved pain relief.
Trang T.H. Tu, Miho Takenoshita, Hirofumi Matsuoka, Takeshi Watanabe, Takayuki Suga, Yuma Aota, Yoshihiro Abiko and Akira Toyofuku : Current management strategies for the pain of elderly patients with burning mouth syndrome: a critical review., BioPsychoSocial Medicine, Vol.13, 2019.
(Summary)
Burning Mouth Syndrome (BMS), a chronic intraoral burning sensation or dysesthesia without clinically evident causes, is one of the most common medically unexplained oral symptoms/syndromes. Even though the clinical features of BMS have been astonishingly common and consistent throughout the world for hundreds of years, BMS remains an enigma and has evolved to more intractable condition. In fact, there is a large and growing number of elderly BMS patients for whom the disease is accompanied by systemic diseases, in addition to aging physical change, which makes the diagnosis and treatment of BMS more difficult. Because the biggest barrier preventing us from finding the core pathophysiology and best therapy for BMS seems to be its heterogeneity, this syndrome remains challenging for clinicians. In this review, we discuss currently hopeful management strategies, including central neuromodulators (Tricyclic Antidepressants - TCAs, Serotonin, and Norepinephrine Reuptake Inhibitors - SNRIs, Selective Serotonin Reuptake Inhibitors - SSRIs, Clonazepam) and solutions for applying non-pharmacology approaches. Moreover, we also emphasize the important role of patient education and anxiety management to improve the patients' quality of life. A combination of optimized medication with a short-term supportive psychotherapeutic approach might be a useful solution.
Takeshi Watanabe, Akinori Kimura and Hidehito Kuroyanagi : Alternative Splicing Regulator RBM20 and Cardiomyopathy., Frontiers in Molecular Biosciences, Vol.5, 2018.
(Summary)
pre-mRNA splicing, raising RBM20 as a potential therapeutic target.
Yojiro Umezaki, Anna Miura, Yukiko Shinohara, Lou Mikuzuki, Shiori Sugawara, Kaoru Kawasaki, Trang T.H. Tu, Takeshi Watanabe, Takayuki Suga, Motoko Watanabe, Miho Takenoshita, Tatsuya Yoshikawa, Akihito Uezato, Toru Nishikawa, Ken Hoshiko, Toru Naito, Haruhiko Motomura and Akira Toyofuku : Clinical characteristics and course of oral somatic delusions: a retrospective chart review of 606 cases in 5 years., Neuropsychiatric Disease and Treatment, Vol.14, 2057-2065, 2018.
(Summary)
Patients with oral cenesthopathy in our clinic were predominantly elderly female patients. Dental treatment in the acute phase of depression might be a risk factor for oral cenesthopathy. Therefore, comprehending the situation of psychiatric disorder and obtaining adequate informed consent might be required to prevent the trouble concerning oral cenesthopathy.
Takeshi Watanabe, Takahiko Nagamine, Lou Mikuzuki, Yuma Aota, Takayuki Suga, Trang T.H. Tu, Miho Takenoshita and Akira Toyofuku : An increase in corrected QT interval may indicate a good clinical response to amitriptyline in female patients with burning mouth syndrome, Neurology and Neurobiology, Vol.1, No.1, 1-3, 2018.
(Summary)
Burning mouth syndrome (BMS) is characterized by a burning sensation of the oral mucosa in the absence of underlying causes. BMS patients can pose a therapeutic challenge to clinicians. Amitriptyline has been a first-line treatment for BMS and is known to prolong corrected QT interval (QTc) in a dose dependent manner. However, little is known about the QTc lengthening effect of amitriptyline at analgesic dosages. The objective of this study was to evaluate changes in QTc in female BMS patients treated with amitriptyline. We conducted a single-center retrospective observational study and evaluated 40 female BMS patients. The QTc interval did not show statistically significant increase with amitriptyline (p=0.1502). However, the change in QTc of amitriptyline-responders was significantly longer than that of non-responders (p=0.0142). The change in QTc may be a non-invasive maker of clinical responses to amitriptyline in female BMS patients.
Trang T.H. Tu, Anna Miura, Yukiko Shinohara, Lou Mikuzuki, Kaoru Kawasaki, Shiori Sugawara, Takayuki Suga, Takeshi Watanabe, Motoko Watanabe, Yojiro Umezaki, Tatsuya Yoshikawa, Haruhiko Motomura, Miho Takenoshita and Akira Toyofuku : Evaluating Burning Mouth Syndrome as a Comorbidity of Atypical Odontalgia: The Impact on Pain Experiences., Pain Practice, Vol.18, No.5, 580-586, 2017.
(Summary)
AO-BMS patients have different epidemiological characteristics, sleep quality, and pain experiences compared to AO-only patients. The presence of psychiatric comorbidities in both groups may exacerbate sleep quality. We suggest that BMS as a comorbid oral disorder in AO patients contributes to a more intensively painful experience.
Anna Miura, Trang T.H. Tu, Yukiko Shinohara, Lou Mikuzuki, Kaoru Kawasaki, Shiori Sugawara, Takayuki Suga, Takeshi Watanabe, Motoko Watanabe, Yojiro Umezaki, Tatsuya Yoshikawa, Haruhiko Motomura, Miho Takenoshita, Hidefumi Maeda and Akira Toyofuku : Psychiatric comorbidities in patients with Atypical Odontalgia., Journal of Psychosomatic Research, Vol.104, 35-40, 2017.
(Summary)
About half of AO patients had comorbid psychiatric disorders. Dental procedures are not necessarily causative factors of AO. In AO patients with comorbid psychiatric disorders, pain might have a larger emotional component than a sensory one. VAS, SDS, and SF-MPQ scores might aid in the noticing of underlying comorbid psychiatric disorders in AO patients.
(Keyword)
Adolescent / Adult / Aged / Aged, 80 and over / Comorbidity / Female / Humans / Male / Mental Disorders / Middle Aged / Pain Measurement / Retrospective Studies / Surveys and Questionnaires / Toothache / Young Adult
Takeshi Watanabe, Shiori Sekine, Isao Naguro, Yusuke Sekine and Hidenori Ichijo : Apoptosis Signal-regulating Kinase 1 (ASK1)-p38 Pathway-dependent Cytoplasmic Translocation of the Orphan Nuclear Receptor NR4A2 Is Required for Oxidative Stress-induced Necrosis., The Journal of Biological Chemistry, Vol.290, No.17, 10791-10803, 2015.
(Summary)
p38 mitogen-activated protein kinases (MAPKs) play important roles in various cellular stress responses, including cell death, which is roughly categorized into apoptosis and necrosis. Although p38 signaling has been extensively studied, the molecular mechanisms of p38-mediated cell death are unclear. ASK1 is a stress-responsive MAP3K that acts as an upstream kinase of p38 and is activated by various stresses, such as oxidative stress. Here, we show that NR4A2, a member of the NR4A nuclear receptor family, acts as a necrosis promoter downstream of ASK1-p38 pathway during oxidative stress. Although NR4A2 is well known as a nucleus-localized transcription factor, we found that it is translocated into the cytosol after phosphorylation by p38. Because the phosphorylation site mutants of NR4A2 cannot rescue the cell death-promoting activity, ASK1-p38 pathway-dependent phosphorylation and subsequent cytoplasmic translocation of NR4A2 may be required for oxidative stress-induced cell death. In addition, NR4A2-mediated cell death does not depend on caspases and receptor-interacting protein 1 (RIP1)-RIP3 complex, suggesting that NR4A2 promotes an RIP kinase-independent necrotic type of cell death. Our findings may enable a more precise understanding of molecular mechanisms that regulate oxidative stress-induced and p38-mediated necrosis.
(Keyword)
Animals / Biological Transport, Active / Cell Line / Cytoplasm / HeLa Cells / Humans / Hydrogen Peroxide / MAP Kinase Kinase Kinase 5 / MAP Kinase Signaling System / Mice / Necrosis / Nuclear Receptor Subfamily 4, Group A, Member 2 / Oxidative Stress / Phosphorylation / RNA, Small Interfering / p38 Mitogen-Activated Protein Kinases
Reactive oxygen species (ROS)-induced activation of Apoptosis signal-regulating kinase 1 (ASK1) plays crucial roles in oxidative stress-mediated cell death through the activation of the JNK and p38 MAPK pathways. However, the regulatory mechanism of ASK1 in the oxidative stress response remains to be elucidated. Here, we identified the kelch repeat protein, Slim, as an activator of ASK1 through a Drosophila misexpression screen. We also performed a proteomics screen and revealed that Kelch domain containing 10 (KLHDC10), a mammalian ortholog of Slim, interacted with Protein phosphatase 5 (PP5), which has been shown to inactivate ASK1 in response to ROS. KLHDC10 bound to the phosphatase domain of PP5 and suppressed its phosphatase activity. Moreover, KLHDC10 was required for H(2)O(2)-induced sustained activation of ASK1 and cell death in Neuro2A cells. These findings suggest that Slim/KLHDC10 is an activator of ASK1, contributing to oxidative stress-induced cell death through the suppression of PP5.
Yusuke Sekine, Shuichi Takagahara, Ryo Hatanaka, Takeshi Watanabe, Haruka Oguchi, Takuya Noguchi, Isao Naguro, Kazuto Kobayashi, Makoto Tsunoda, Takashi Funatsu, Hiroshi Nomura, Takeshi Toyoda, Norio Matsuki, Erina Kuranaga, Masayuki Miura, Kohsuke Takeda and Hidenori Ichijo : p38 MAPKs regulate the expression of genes in the dopamine synthesis pathway through phosphorylation of NR4A nuclear receptors., Journal of Cell Science, Vol.124, No.Pt 17, 3006-3016, 2011.
(Summary)
In Drosophila, the melanization reaction is an important defense mechanism against injury and invasion of microorganisms. Drosophila tyrosine hydroxylase (TH, also known as Pale) and dopa decarboxylase (Ddc), key enzymes in the dopamine synthesis pathway, underlie the melanin synthesis by providing the melanin precursors dopa and dopamine, respectively. It has been shown that expression of Drosophila TH and Ddc is induced in various physiological and pathological conditions, including bacterial challenge; however, the mechanism involved has not been fully elucidated. Here, we show that ectopic activation of p38 MAPK induces TH and Ddc expression, leading to upregulation of melanization in the Drosophila cuticle. This p38-dependent melanization was attenuated by knockdown of TH and Ddc, as well as by that of Drosophila HR38, a member of the NR4A family of nuclear receptors. In mammalian cells, p38 phosphorylated mammalian NR4As and Drosophila HR38 and potentiated these NR4As to transactivate a promoter containing NR4A-binding elements, with this transactivation being, at least in part, dependent on the phosphorylation. This suggests an evolutionarily conserved role for p38 MAPKs in the regulation of NR4As. Thus, p38-regulated gene induction through NR4As appears to function in the dopamine synthesis pathway and may be involved in immune and stress responses.
Takeshi Watanabe, Mette Sieg, Sigrid Juhl Lunde, Pankaj Taneja, Lene Baad-Hansen, Maria Pigg and Lene Vase : Hvad er noceboeffekten, og spiller den en rolle i odontologien? En narrativ oversigt, tandlaegebladet.dk, 2023.
(Tokushima University Institutional Repository: 118087)
3.
Takeshi Watanabe : Researcher's lounge 2021-2022: What is the nocebo effect and does it apply to dentistry?-A narrative review, Pre Symptomatic Medicine and Anti Aging, Vol.31, 101, 2022.
Takahiko Nagamine and Takeshi Watanabe : The catastrophic perception of pain in burning mouth syndrome may be associated with sympathetic tone as indicated by the QTc interval, Innovations in Clinical Neurosciences, 2024.
Takeshi Watanabe, Hidenori Ichijo and Hideki Nishitoh : 神経変性疾患と小胞体ストレス, Bio Clinica, Vol.26, No.7, 612-616, Jul. 2011.
Proceeding of International Conference:
1.
Takeshi Watanabe : Placebo/Nocebo research in the post-GWAS era, 4th International Conference of the Society for Interdisciplinary Placebo Studies (SIPS), Duisburg, Germany, May 2023.
2.
Nguyen Van Tien, Kokichi Arisawa, Sakurako Kamano, Takeshi Watanabe and Masashi Ishizu : Association of metabolic syndrome and metabolically unhealthy obesity with cancer mortality, Asia Pacific Conference 2022, Beppu, Dec. 2022.
3.
Takeshi Watanabe, Mette Sieg, Sigrid Juhl Lunde, Mads Persson, Pankaj Taneja, Lene Baad-Hansen, Maria Pigg and Lene Vase : Nocebo response in Dentistry: A systematic review and meta-analysis, IASP 2022 World Congress on Pain, Toronto, Canada, 19-23, September, Toronto, Sep. 2022.
Takeshi Watanabe, Mette Sieg, Sigrid Juhl Lunde, Pankaj Taneja, Lene Baad-Hansen and Lene Vase : Adverse events in placebo groups of clinical trials of analgesics for post-operative dental pain: A systematic review and meta-analysis, 3rd International conference of Society for Interdisciplinary Placebo Studies (SIPS), the the University of Maryland, Baltimore U.S.A., May 2021.
Proceeding of Domestic Conference:
1.
Takeshi Watanabe : Coffee and metabolic phenotypes: A cross-sectional analysis of the Japan multi-institutional collaborative cohort (J-MICC) study, 令和5年度コホート・生体試料支援プラットフォーム若手支援研究成果発表会, Feb. 2024.
2.
Takeshi Watanabe : Coffee and metabolic phenotypes: A cross-sectional analysis of the Japan multi-institutional collaborative cohort (J-MICC) study, 2023 年度科学研究費補助⾦「コホート・⽣体試料⽀援プラットフォーム」⽀援に係る会議 ⽇本多施設共同コーホート(J-MICC)研究2023 年度 第2回全体会議, Dec. 2023.
3.
Sakurako Kamano, Kokichi Arisawa, Masashi Ishizu, Takeshi Watanabe and Nguyen Van Tien : 大豆製品およびイソフラボン摂取量と糖尿病罹患との関連:J-MICC Study, 第33回日本疫学会学術総会, Feb. 2023.
4.
Takeshi Watanabe, Kokichi Arisawa, Tien Van Nguyen, Masashi Ishizu and Sakurako Kamano : Coffee and metabolic phenotypes: A cross-sectional analysis of the Japan multi-institutional collaborative cohort (J-MICC) study, The 33rd annual scientific meeting of the Japan Epidemiological Association, Feb. 2023.
5.
Sakurako Kamano, Kokichi Arisawa, Masashi Ishizu, Takeshi Watanabe, NGUYEN VAN TIEN and for the J-MICC Study Group : 朝食欠食および睡眠時間とメタボリック症候群との関連:J-MICC Study, 第264回徳島医学会学術集会, Feb. 2022.
6.
Tien Van Nguyen, Kokichi Arisawa, Sakurako Kamano, Takeshi Watanabe, Masashi Ishizu and for the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study Group : Associations of metabolic syndrome and metabolically unhealthy obesity with cancer mortality: Results of prospective cohort study in Japanese population, 第264回徳島医学会学術集会, Feb. 2022.
7.
Tien Van Nguyen, Kokichi Arisawa, Sakurako Katsuura-Kamano, Takeshi Watanabe, Masashi Ishizu and for the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study Group : Associations of metabolic syndrome and metabolically unhealthy obesity with cancer mortality, 第32回日本疫学会学術総会, Jan. 2022.
8.
Sakurako Kamano, Kokichi Arisawa, Masashi Ishizu, Takeshi Watanabe, NGUYEN TIEN VAN and for the J-MICC Study Group : 大豆製品およびイソフラボン摂取量と全死亡・がん死亡との関連:J-MICC Study, 第32回日本疫学会学術総会, Jan. 2022.