Role of A-Kinase Anchoring Protein 12 in the Central Nervous System

Shintaro Kimura,Josephine Lok,Irwin H. Gelman,Eng H. Lo,Ken Arai 대한신경과학회 2023 Journal of Clinical Neurology Vol.19 No.4

A-kinase anchoring protein (AKAP) 12 is a scaffolding protein that anchors various signaling proteins to the plasma membrane. These signaling proteins include protein kinase A, protein kinase C, protein phosphatase 2B, Src-family kinases, cyclins, and calmodulin, which regulate their respective signaling pathways. AKAP12 expression is observed in the neurons, astrocytes, endothelial cells, pericytes, and oligodendrocytes of the central nervous system (CNS). Its physiological roles include promoting the development of the blood–brain barrier, maintaining white-matter homeostasis, and even regulating complex cognitive functions such as long-term memory formation. Under pathological conditions, dysregulation of AKAP12 expression levels may be involved in the pathology of neurological diseases such as ischemic brain injury and Alzheimer’s disease. This minireview aimed to summarize the current literature on the role of AKAP12 in the CNS.

Molecular pathogenesis of Spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins

Bin, Bum-Ho,Hojyo, Shintaro,Hosaka, Toshiaki,Bhin, Jinhyuk,Kano, Hiroki,Miyai, Tomohiro,Ikeda, Mariko,Kimura-Someya, Tomomi,Shirouzu, Mikako,Cho, Eun-Gyung,Fukue, Kazuhisa,Kambe, Taiho,Ohashi, Wakana BlackWell Publishing Ltd 2014 EMBO molecular medicine Vol.6 No.8

<P>The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD-EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13<SUP>G64D</SUP>, in which Gly at amino acid position 64 is replaced by Asp, and ZIP13<SUP>ΔFLA</SUP>, which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13<SUP>G64D</SUP> and ZIP13<SUP>ΔFLA</SUP> protein levels are decreased by degradation via the valosin-containing protein (VCP)-linked ubiquitin proteasome pathway. The inhibition of degradation pathways rescued the protein expression levels, resulting in improved intracellular Zn homeostasis. Our findings uncover the pathogenic mechanisms elicited by mutant ZIP13 proteins. Further elucidation of these degradation processes may lead to novel therapeutic targets for SCD-EDS.</P>

Prevalence of Irritable Bowel Syndrome in Japan, China, and South Korea: An International Cross-sectional Study

Atsushi Takeoka,Takuya Kimura,Shintaro Hara,Toyohiro Hamaguchi,Shin Fukudo,Jun Tayama 대한소화기 기능성질환∙운동학회 2023 Journal of Neurogastroenterology and Motility (JNM Vol.29 No.2

Background/AimsSymptoms of irritable bowel syndrome (IBS), a common gut-brain interaction disorder, deteriorate patients’ quality of life and increase medical needs; therefore, IBS represents a significant global burden. The estimated global prevalence is approximately 10%; however, accumulated evidence shows international heterogeneity. In this study, we have described and compared the prevalence of IBS in 3 East Asian countries: Japan (Tokyo and Fukuoka), China (Beijing), and South Korea (Seoul). MethodsWe conducted an internet-based cross-sectional survey of the urban population aged > 20 years in the abovementioned countries. We recruited equal numbers of age- (20s-60s) and sex-matched participants (3910 residents). IBS was diagnosed according to the Rome III criteria, and the subtypes were analyzed. ResultsThe overall prevalence of IBS with 95% CI was 12.6% (11.6-13.7); the prevalence was significantly different across Japan, China, and South Korea (14.9% [13.4-16.5], 5.5% [4.3-7.1], and 15.6% [13.3-18.3], respectively) (P < 0.001). Furthermore, 54.9% of patients were male. IBS-mixed was the most prevalent subtype; the prevalence of other subtypes varied. ConclusionsThe overall prevalence of IBS in the 3 countries was slightly higher than the global prevalence, and it was significantly lower in China than in Japan and South Korea. IBS prevalence was the highest and lowest among individuals in their 40s and 60s, respectively. Male individuals had a higher prevalence of IBS with diarrhea. Further studies are needed to elucidate the factors associated with this regional heterogeneity.

Chemoradiotherapy followed by consolidation chemotherapy involving paclitaxel and carboplatin and in FIGO stage IIIB/IVA cervical cancer patients

Seiji Mabuchi,Fumiaki Isohashi,Mika Okazawa,Fuminori Kitada,Shintaro Maruoka,Kazuhiko Ogawa,Tadashi Kimura 대한부인종양학회 2017 Journal of Gynecologic Oncology Vol.28 No.1

Objective: To evaluate the efficacy and toxicity of paclitaxel plus carboplatin (TC)-based concurrent chemoradiotherapy (CCRT) followed by consolidation chemotherapy in the International Federation of Gynecology and Obstetrics (FIGO) stage IIIB/IVA cervical cancer patients. Methods: We reviewed the medical records of FIGO stage IIIB/IVA cervical cancer patients (n=30) who had been intended to be treated with TC-based CCRT followed by consolidation chemotherapy (TC-CCRT-group) from April 2012–May 2016. Patients who had been treated with CCRT involving a single platinum agent (CCRT-group; n=52) or definitive radiotherapy alone (RT-group; n=74) from January 1997–September 2012 were also identified and used as historical controls. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. Results: Of the 30 patients included in the TC-CCRT-group, 22 patients (73.3%) completed the planned TC-based CCRT. The most frequently observed acute grade 3/4 hematological toxicities were leukopenia and neutropenia, and diarrhea was the most common acute grade 3/4 non-hematological toxicity. After a median follow-up of 35 months, 9 patients (30.0%) had developed recurrent disease. The patients’ estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 67.9% and 90.8%, respectively. In comparisons with historical control groups, the survival outcomes of TC-CCRT-group was significantly superior to CCRT-group in terms of OS (p=0.011) and significantly superior to RT-group in terms of both PFS (p=0.009) and OS (p<0.001). Conclusion: TC-based CCRT followed by consolidation chemotherapy is safe and effective. A randomized controlled study needs to be conducted to further evaluate the efficacy of this multimodal approach in this patient population.

Human Leukocyte Antigens and Biomarkers in Type 1 Diabetes Mellitus Induced by Immune-checkpoint Inhibitors

Hidefumi Inaba,Yosuke Kaido,Saya Ito,Tomonao Hirobata,Gen Inoue,Takakazu Sugita,Yuki Yamamoto,Masatoshi Jinnin,Hiroaki Kimura,Tomoko Kobayashi,Shintaro Iwama,Hiroshi Arima,Takaaki Matsuoka 대한내분비학회 2022 Endocrinology and metabolism Vol.37 No.1

Background: Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear. Methods: In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021. Results: Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P=0.022; 11/14 vs. 7/26, P=0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset. Conclusion: Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.