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Role of CD34 in calcification of human aortic valve interstitial cells from patients with aortic valve stenosis
Get PDFVarious osteogenic factors are involved in ectopic human aortic valve calcification; however, the key cell species involved in calcification remains unclear. In a previous study, we reported that mesenchymal stem (CD73, 90, 105) and endothelial (VEGFR2) cell markers are positive in almost all human aortic valve interstitial cells (HAVICs) obtained from a patient with calcified aortic valve stenosis (CAVS). Further, CD34-negative HAVICs are highly sensitive to calcification stimulations. Here, we aimed to pathophysiologically clarify the role of CD34 in HAVICs obtained from individual patients with severe CAVS. A DNA microarray between CD34-positive and CD34-negative HAVICs, separated by fluorescence-activated cell sorting, indicated that tenascin X (TNX) mRNA expression significantly decreased in CD34-negative cells. Furthermore, the inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1β significantly downregulated CD34 expression in HAVICs. TGF-β, a key cytokine of endothelial-mesenchymal transition, did not affect HAVIC calcification. CD34 overexpression strongly inhibited TNF-α- and IL-1β-induced calcification and maintained TNX mRNA expression. These results suggest one possibility that CD34 is an inhibitory regulator of valve calcification. Furthermore, TNF-α- and IL-1β-induced CD34 downregulation in HAVICs contributes to HAVIC calcification by downregulating TNX protein expression.弘前大学博士（医学）Author(s)：Shihu Men , Zaiqiang Yu , Xu Liu , Kazuyuki Daitoku , Mayuki Tachizaki , Shogo Kawaguchi , Tadaatsu Imaizumi , Masahito Minakawa , Kazuhiko Seya
掲載誌：Journal of Pharmacological Sciences（156(3), 196-207）[日本薬理学会]
出版社：ELSEVIER
© 2024 . This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0
Oligoribonucleotide interference-PCR-based methods for the sensitive and accurate detection of KRAS mutations
Get PDFPancreatic cancer is an aggressive malignancy with a poor prognosis. Single-nucleotide mutations in the KRAS gene are detected in the majority of patients with pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. Identifying KRAS mutations by liquid biopsy could be effective for detecting de novo and recurrent PDAC; however, sensitive and accurate detection remains challenging. We examined the utility of oligoribonucleotide interference-PCR (ORNi-PCR) followed by real-time PCR or droplet digital PCR (ddPCR) for detecting KRAS single-nucleotide mutations by liquid biopsy. A model of cell-free DNA was used to demonstrate that the ORNi-PCR-based methods are more sensitive and accurate for detecting KRAS mutant DNA than conventional real-time PCR or ddPCR. ORNi-PCR-based methods could be useful for early detection of de novo and recurrent PDAC by liquid biopsy for cancer diagnosis.弘前大学博士（医学）Author(s): Hiroaki Fujita, Toshitsugu Fujita, Keinosuke Ishido, Kenichi Hakamada, Hodaka Fuji
The relationship of polyunsaturated and monounsaturated fatty acids intake and serum concentrations on inhalant allergen sensitization and allergic rhinitis development
Get PDFBackground
The increasing prevalence of allergic rhinitis may be attributed to lifestyle changes such as dietary habits. Regarding dietary factors, n-3 and n-6 polyunsaturated fatty acids (PUFAs) are considered to be involved in the pathogenesis. Therefore, we examined whether the intake and serum concentrations of fatty acids affect inhaled allergen sensitization and the development of allergic rhinitis.
Methods
In total, 571 participants (20–69 years) from the Iwaki Health Promotion Project, a community-based project in 2022, were surveyed. Based on the results of PUFA intake and serum fatty acid concentrations obtained using a self-administered diet-history questionnaire, we examined whether n-3 or n-6 PUFAs were involved in reducing or increasing the risk of sensitization, respectively, and developing the disease. We also analyzed whether monounsaturated fatty acids—palmitoleic acid and oleic acid—were risk factors for sensitization and development. Univariate dietary intake, serum concentration, and logistic regression analyses were performed to identify the risk factors.
Results
Our study revealed that higher serum concentrations of n-3 PUFAs were associated with a decreased risk of developing rhinitis, but had no effect on allergen sensitization in younger age group <50 years. Furthermore, palmitoleic acid had increased sensitization, and oleic acid may also increase the risk of the allergen sensitization.
Conclusions
n-3 PUFAs may reduce the risk of developing allergic rhinitis. Notably, palmitoleic acid may be a new risk factor that increases the risk of inhalant allergen sensitization and allergic rhinitis. These findings are significant in understanding the role of dietary factors in allergic rhinitis.弘前大学博士（医学）Author(s): Chihiro Nakamura, Atsushi Matsubara, Ayami Nomura, Junko Takahata, Kaori Sawada, Shigeyuki Nakaji
Allergology International
Available online 25 February 2025
DOI: https://doi.org/10.1016/j.alit.2024.12.00
Toll-Like Receptor 7-Expressed Macrophages Are Involved in the Pathogenesis of Esophageal Achalasia and Esophagogastric Junction Outflow Obstruction
Get PDFIntroduction: Esophageal achalasia is a typical esophageal motility disorder (EMD). Although viral infections have been hypothesized to play a role in the pathogenesis of esophageal achalasia, its etiology remains unclear. This study used esophageal muscle layer specimens collected during per-oral endoscopic myotomy (POEM) procedures to investigate the association between esophageal achalasia and esophagogastric junction outflow obstruction (EGJOO) and pattern recognition receptors. Methods: Patients with esophageal achalasia and EGJOO who underwent POEM were allocated to the EMD group. Biopsies of the inner circular muscle were conducted during the POEM procedure. The control group comprised individuals diagnosed with esophageal squamous cell carcinoma who underwent surgical resection. Expression of pattern recognition receptors, including Toll-like receptor (TLR) 7, was examined by polymerase chain reaction. Immunohistochemical staining was performed to determine TLR7 expression sites in the esophageal muscle layer, and the relationship between TLR7 mRNA expression and clinical score was investigated. Results: Our analysis revealed a notable upregulation of TLR7 mRNA levels within the muscle layer of esophageal achalasia and EGJOO, in contrast to those of control specimens. In contrast, the correlation between TLR7 and clinical score was not significant. Immunohistochemical staining revealed increased numbers of TLR7-expressing macrophages between the muscle layers. Conclusions: TLR7-expressing macrophages are involved in the innate immune response underlying esophageal achalasia and EGJOO. This result will lead to the elucidation of new pathogenetic mechanisms and the development of novel therapeutic targets.弘前大学博士（医学）Author(s): Masatoshi Kaizuka; Tetsuya TatsutaCorresponding Author; Shogo Kawaguchi ; Tadashi Yoshizawa; Shukuko Yoshida; Tetsuyuki Tateda; Yohei Sawada; Shinji Ota; Shiro Hayamizu; Keisuke Hasui; Hidezumi Kikuchi; Hiroto Hiraga; Daisuke Chinda; Takahiro Muroya; Kenichi Hakamada; Hiroshi Kijima; Tatsuya Mikami; Shinsaku Fukuda; Hirotake Sakurab
Chondroitin sulfate chain of urinary trypsin inhibitor plays an important role in anti-inflammatory effects
Get PDFAim: This study aimed to investigate the role of the chondroitin sulfate (ChS) chain in the anti-inflammatory effect of urinary trypsin inhibitors (UTIs), identify ChS structures that enhance the anti-inflammatory activity of UTIs, and develop a more effective treatment for preterm birth.
Methods: ChS chain-remodeled UTIs were prepared by hydrolysis and/or transglycosylation reaction of testicular hyaluronidase. Uterine cervical fibroblasts were treated with native and ChS-remodeled UTIs and incubated with lipopolysaccharide to induce inflammation. To assess anti-inflammatory effects, interleukin-8 (IL-8) concentrations in the culture supernatants were measured by enzyme-linked immunosorbent assay.
Results: Compared with controls without UTIs, Ch6S-transferred UTI at the nonreducing terminal significantly suppressed IL-8 release. Other UTIs showed limited suppression.
Conclusion: The Ch6S chain at the nonreducing terminus of UTI enhances its antiinflammatory effect. This finding could lead to the development of innovative treatments for preterm birth.弘前大学博士（医学）Author(s): Tomoe Kodama, Ikuko Kakizaki, Kanji Tanaka, Seigo Tanaka, Asami Ito-Fukuyama, Shinichiro Suto, Saki Kurotaki, Ryuto Tsushima, Maki Sato, Ryoki Takahashi, Yoshihito Yokoyama
掲載誌：
巻号頁： Volume 13 Issue 1 Pages 10-16
Published: February 28, 2025
Released on J-STAGE: February 28, 2025
Advance online publication: January 21, 2025
DOI: https://doi.org/10.14390/jsshp.HRP2024-016
Hypertension Research in Pregnancy © 2025 Japan Society for the Study of Hypertension in Pregnanc
Involvement of Megasphaera in the Oral Microbiome and Dyslipidemia Onset: Evidence from a Community-Based Study in Japan
No full textDyslipidemia is a major risk factor for cardiovascular diseases and is influenced by genetic and environmental factors, including diet. Emerging research suggests a link between the gut microbiome and metabolic disorders. While the connection between the gut microbiota and dyslipidemia is well documented, the specific relationship between oral bacteria and dyslipidemia has not been thoroughly investigated. This study aimed to identify oral bacterial species associated with dyslipidemia in a community-based Japanese population. We conducted a metagenomic analysis on tongue coating samples from 763 participants in the Iwaki Health Promotion Project, which were collected during health checkups in 2017 and 2019. Dyslipidemia was diagnosed using standard lipid level criteria. The oral microbiome was analyzed via 16S rDNA amplicon sequencing. Statistical analyses included multiple regression and β diversity assessments. Our analysis revealed that the abundances of several bacterial genera, including Veillonella, Atopobium, Stomatobaculum, Tanneralla, and Megasphaera, are significantly associated with dyslipidemia. A higher relative abundance of Megasphaera was specifically observed in individuals with dyslipidemia. Moreover, Megasphaera abundance was closely associated with the onset of dyslipidemia (p = 0.038, odds ratio: 1.005, 95% confidence interval: 1.000–1.009), suggesting its role in metabolic regulation. This study revealed a significant association between the abundance of specific oral bacteria and dyslipidemia, suggesting the potential of using the oral microbiota as a biomarker for the early detection and management of dyslipidemia. Future research should explore the mechanisms through which oral bacteria influence lipid metabolism and the potential for microbioma-based therapies.弘前大学博士（医学）Author(s): Takagi, Koki ; Tamura, Yoshihiro ; Narita, Norihiko ; Komatsu, Shotaro ; Yamazaki, Shunya ; Matsumura, Akihiro ; Kubota, Kosei ; Matsumiya, Tomoh ; Sawada, Kaori ; Nakaji, Shigeyuki ; Mikami, Tatsuya ; Kobayashi, Watar
Greater medial proximal tibial slope is associated with bone marrow lesions in middle‑aged women with early knee osteoarthritis
Get PDF弘前大学博士（医学）掲載誌：Journal of Orthopaedics and Traumatology 2023 Nov 28;24(1):60
Tryptophan metabolism and small fibre neuropathy: a correlation study
Get PDFSmall nerve fibres located in the epidermis sense pain. Dysfunction of these fibres decreases the pain threshold known as small fibre neuropathy. Diabetes mellitus is accompanied by metabolic changes other than glucose, synergistically eliciting small fibre neuropathy. These findings suggest that various metabolic changes may be involved in small fibre neuropathy. Herein, we explored the correlation between pain sensation and changes in plasma metabolites in healthy Japanese subjects. The pain threshold evaluated from the intraepidermal electrical stimulation was used to quantify pain sensation in a total of 1021 individuals in the 2017 Iwaki Health Promotion Project. Participants with a pain threshold evaluated from the intraepidermal electrical stimulation index <0.20 mA were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-low group (n = 751); otherwise, they were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation indexhigh group (n = 270). Metabolome analysis of plasma was conducted using capillary electrophoresis time-of-flight mass spectrometry. The metabolite set enrichment analysis revealed that the metabolism of tryptophan was significantly correlated with the pain threshold evaluated from the intraepidermal electrical stimulation index in all participants (P < 0.05). The normalized level of tryptophan was significantly decreased in participants with a high pain threshold evaluated from the intraepidermal electrical stimulation index. In addition to univariate linear regression analyses, the correlation between tryptophan concentration and the pain threshold evaluated from the intraepidermal electrical stimulation index remained significant after adjustment for multiple factors (β = −0.07615, P < 0.05). These findings indicate that specific metabolic changes are involved in the deterioration of pain thresholds. Here, we show that abnormal tryptophan metabolism is significantly correlated with an elevated pain threshold evaluated from the intraepidermal electrical stimulation index in the Japanese population. This correlation provides insight into the pathology and clinical application of small fibre neuropathy.弘前大学博士（医学）Author: Hanae Kushibiki, Hiroki Mizukami, Sho Osonoi, Yuki Takeuchi, Takanori Sasaki, Saori Ogasawara, Kanichiro Wada, Shin Midorikawa, Masaki Ryuzaki, Zhenchao Wang, Takahiro Yamada, Keisuke Yamazaki, Takefusa Tarusawa, Taiyo Tanba, Tatsuya Mikami, Atsushi Matsubara, Yasuyuki Ishibashi, Kenichi Hakamada and Shigeyuki NakajiCitation: Brain communications, 6(2):fcae103; 202
Distinction of ALK fusion gene- and EGFR mutation-positive lung cancer with tumor markers
Get PDFBackground: It is difficult to predict gene mutations individually based on clinical background alone. Tumor markers may help to predict each gene mutation. Identifying tumor markers that can predict gene mutation will facilitate timely genetic testing and intervention.
Methods: We selected 134 cases of advanced or recurrent ALK-positive and 172 cases of advanced or recurrent EGFR-positive lung cancer from our clinical database. The cutoff values for the tumor markers were defined as 5.0 ng/mL or higher for carcinoembryonic antigen (CEA) and 3.5 ng/mL or higher for soluble fragment of cytokeratin 19 (CYFRA21-1) in accordance with the institutional standards. A positive CYFRA21-1:CEA ratio was defined as 0.7 or higher.
Results: The CEA-positivity rate was 49% for ALK-positive lung cancers and 73% for EGFR-positive lung cancers, which was significantly different (p < 0.001). The CYFRA21-1 positivity rate was significantly higher in ALK-positive lung cancer (36%) compared with EGFR-positive lung cancer (23%) (p = 0.034). The median CYFRA21-1:CEA ratio was 0.395 for the ALK group, which was significantly higher compared with 0.098 for the EGFR group (p < 0.001). These trends were similar when excluding histology other than adenocarcinoma. The median time-to-treatment failure (TTF) for initial tyrosine kinase inhibitor (TKI) therapy was 308 days for the high CYFRA21-1:CEA ratio group and 617 days for the low CYFRA21-1:CEA ratio group for ALK-positive lung cancer (p = 0.100).
Conclusions: A higher proportion of patients with ALK-positive lung cancer were CYFRA21-1 positive and had higher CYFRA21-1:CEA ratios compared with EGFRpositive lung cancer patients.弘前大学博士（医学）Author: Takahiro Akita, Ryo Ariyasu, Keiki Miyadera, Ayu Kiritani, Ryosuke Tsugitomi, Yoshiaki Amino, Ken Uchibori, Satoru Kitazono, Noriko Yanagitani, Sadatomo Tasaka, Makoto NishioCitation: Thoracic Cancer 15(10):788-796, 2024
