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Article ; Online: Detection and identification of factors in the atrium responsible for blood pressure regulation in patients with hypertension.

Yoshimura, Kenshi / Mengyan, Wei / Kume, Shinichiro / Kurokawa, Tatsuki / Miyamoto, Shinji / Mizukami, Yoichi / Ono, Katsushige

Heart and vessels

2024 Volume 39, Issue 5, Page(s) 464–474

Abstract: Resection of the left atrial appendage reportedly improves blood pressure in patients with hypertension. This study aimed to validate the transcriptional profiles of atrial genes responsible for blood pressure regulation in patients with hypertension as ... ...

Abstract	Resection of the left atrial appendage reportedly improves blood pressure in patients with hypertension. This study aimed to validate the transcriptional profiles of atrial genes responsible for blood pressure regulation in patients with hypertension as well as to identify the molecular mechanisms in rat biological systems. RNA sequencing data of left atrial appendages from patients with (n = 6) and without (n = 6) hypertension were subjected to unsupervised principal component analysis (PCA). Reduction of blood pressure was reflected by third and ninth principal components PC3 and PC9, and that eighteen transcripts, including endothelin-1, were revealed by PCA-based pathway analysis. Resection of the left atrial appendage in hypertensive rats improved their blood pressure accompanied by a decrease in serum endothelin-1 concentration. Expression of the endothelin-1 gene in the atrium and atrial appendectomy could play roles in blood pressure regulation in humans and rats.
MeSH term(s)	Humans ; Rats ; Animals ; Blood Pressure ; Endothelin-1 ; Hypertension/complications ; Heart Atria ; Atrial Appendage
Chemical Substances	Endothelin-1
Language	English
Publishing date	2024-03-07
Publishing country	Japan
Document type	Journal Article
ZDB-ID	89678-0
ISSN	1615-2573 ; 0910-8327 ; 0935-736X
ISSN (online)	1615-2573
ISSN	0910-8327 ; 0935-736X
DOI	10.1007/s00380-024-02362-0
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Article ; Online: Bardoxolone methyl prevents metabolic dysfunction-associated steatohepatitis by inhibiting macrophage infiltration.

Onuma, Kazuhiro / Watanabe, Kenji / Isayama, Keishiro / Ogi, Sayaka / Tokunaga, Yasunori / Mizukami, Yoichi

British journal of pharmacology

2024

Abstract: Background and purpose: Bardoxolone methyl (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me) is a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which induces the expression of antioxidative-associated ... ...

Abstract	Background and purpose: Bardoxolone methyl (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me) is a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which induces the expression of antioxidative-associated genes. CDDO-Me exerts protective effects against chronic inflammatory diseases in the kidneys and lungs. However, its pharmacological effects on metabolic dysfunction-associated steatohepatitis (MASH) caused by fat accumulation remain unknown. In this study, we examined the hepatoprotective effects of CDDO-Me in a diet-induced MASH mouse model and elucidated its pharmacological mechanisms using RNA-seq analysis. Experimental approach: CDDO-Me was orally administered to mice fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), and histological, biochemical, and transcriptomic analyses were performed on livers of mice that developed MASH. Key results: CDDO-Me administration induced the expression of antioxidant genes and cholesterol transporters downstream of Nrf2 and significantly prevented the symptoms of MASH. Whole-transcriptome analysis revealed that CDDO-Me inhibited the inflammatory pathway that led to phagocyte recruitment, in addition to activating the Nrf2-dependent pathway. Among inflammatory pathways, CC chemokine ligands (CCL)3 and CCL4, which are downstream of NF-κB and are associated with the recruitment of macrophages expressing CC chemokine receptors (CCR)1 and CCR5, were released into the blood in MASH mice. However, CDDO-Me directly inhibited the expression of CCL3-CCR1 and CCL4-CCR5 in macrophages. Conclusions and implications: Overall, we revealed the potent hepatoprotective effect of CDDO-Me in a MASH mouse model and demonstrated that its pharmacological effects were closely associated with a reduction of macrophage infiltration, through CCL3-CCR1 and CCL4-CCR5 inhibition, in addition to Nrf2-mediated hepatoprotective effects.
Language	English
Publishing date	2024-04-10
Publishing country	England
Document type	Journal Article
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.16374
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Article ; Online: G-protein-coupled estrogen receptor prevents nuclear factor-kappa B promoter activation by Helicobacter pylori cytotoxin-associated gene A in gastric cancer cells.

Okamoto, Mariko / Miura, Atsushi / Ito, Ryota / Kamada, Toshiki / Mizukami, Yoichi / Kawamoto, Keiko

The Journal of veterinary medical science

2023 Volume 85, Issue 12, Page(s) 1348–1354

Abstract: Helicobacter pylori is a well-known pathogen that causes chronic gastritis, leading to the development of gastric cancer. This bacterium has also been detected in dogs, and symptoms similar to those in humans have been reported. The cytotoxin-associated ... ...

Abstract	Helicobacter pylori is a well-known pathogen that causes chronic gastritis, leading to the development of gastric cancer. This bacterium has also been detected in dogs, and symptoms similar to those in humans have been reported. The cytotoxin-associated gene A (CagA) is involved in pathogenesis through aberrant activation of host signal transduction, including the nuclear factor-kappa B (NF-κB) pathway. We have previously shown the anti-inflammatory effect of the G-protein-coupled estrogen receptor (GPER) via inhibiting of NF-κB activation in several cells. Therefore, here, we investigated the effect of GPER on CagA-mediated NF-κB promoter activity and showed that CagA overexpression in gastric cancer cells activated the NF-κB reporter and induced interleukin 8 (il-8) expression, both of which were inhibited by the GPER agonist.
MeSH term(s)	Animals ; Dogs ; Humans ; Cytotoxins/metabolism ; Dog Diseases/metabolism ; Gastric Mucosa/metabolism ; GTP-Binding Proteins/metabolism ; Helicobacter Infections/metabolism ; Helicobacter Infections/veterinary ; Helicobacter pylori/genetics ; Helicobacter pylori/metabolism ; Interleukin-8/genetics ; NF-kappa B/metabolism ; Receptors, Estrogen/genetics ; Receptors, Estrogen/metabolism ; Stomach Neoplasms/genetics ; Stomach Neoplasms/metabolism ; Stomach Neoplasms/veterinary
Chemical Substances	Cytotoxins ; GTP-Binding Proteins (EC 3.6.1.-) ; Interleukin-8 ; NF-kappa B ; Receptors, Estrogen
Language	English
Publishing date	2023-11-13
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1071753-5
ISSN	1347-7439 ; 0916-7250
ISSN (online)	1347-7439
ISSN	0916-7250
DOI	10.1292/jvms.23-0054
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Article ; Online: Human TMEM2 is not a catalytic hyaluronidase, but a regulator of hyaluronan metabolism via HYBID (KIAA1199/CEMIP) and HAS2 expression.

Sato, Shinya / Miyazaki, Megumi / Fukuda, Shinji / Mizutani, Yukiko / Mizukami, Yoichi / Higashiyama, Shigeki / Inoue, Shintaro

The Journal of biological chemistry

2023 Volume 299, Issue 6, Page(s) 104826

Abstract: Cutaneous hyaluronan (HA) is depolymerized to intermediate sizes in the extracellular matrix, and further fragmented in the regional lymph nodes. Previously, we showed that the HA-binding protein involved in HA depolymerization (HYBID), also known as ... ...

Abstract	Cutaneous hyaluronan (HA) is depolymerized to intermediate sizes in the extracellular matrix, and further fragmented in the regional lymph nodes. Previously, we showed that the HA-binding protein involved in HA depolymerization (HYBID), also known as KIAA1199/CEMIP, is responsible for the first step of HA depolymerization. Recently, mouse transmembrane 2 (mTMEM2) with high structural similarity to HYBID was proposed to be a membrane-bound hyaluronidase. However, we showed that the knockdown of human TMEM2 (hTMEM2) conversely promoted HA depolymerization in normal human dermal fibroblasts (NHDFs). Therefore, we examined the HA-degrading activity and function of hTMEM2 using HEK293T cells. We found that human HYBID and mTMEM2, but not hTMEM2, degraded extracellular HA, indicating that hTMEM2 does not function as a catalytic hyaluronidase. Analysis of the HA-degrading activity of chimeric TMEM2 in HEK293T cells suggested the importance of the mouse GG domain. Therefore, we focused on the amino acid residues that are conserved in active mouse and human HYBID and mTMEM2 but are substituted in hTMEM2. The HA-degrading activity of mTMEM2 was abolished when its His248 and Ala303 were simultaneously replaced by the corresponding residues of inactive hTMEM2 (Asn248 and Phe303). In NHDFs, enhancement of hTMEM2 expression by proinflammatory cytokines decreased HYBID expression and increased hyaluronan synthase 2-dependent HA production. The effects of proinflammatory cytokines were abrogated by hTMEM2 knockdown. A decreased HYBID expression by interleukin-1β and transforming growth factor-β was canceled by hTMEM2 knockdown. In conclusion, these results indicate that hTMEM2 is not a catalytic hyaluronidase, but a regulator of HA metabolism.
MeSH term(s)	Animals ; Humans ; Mice ; Cytokines ; HEK293 Cells ; Hyaluronan Synthases/genetics ; Hyaluronic Acid/metabolism ; Hyaluronoglucosaminidase/genetics ; Hyaluronoglucosaminidase/metabolism
Chemical Substances	Cytokines ; HAS2 protein, human (EC 2.4.1.212) ; Hyaluronan Synthases (EC 2.4.1.212) ; Hyaluronic Acid (9004-61-9) ; Hyaluronoglucosaminidase (EC 3.2.1.35) ; CEMIP2 protein, human ; CEMIP protein, human (EC 3.2.1.35)
Language	English
Publishing date	2023-05-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.104826
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Article ; Online: Gait training with a wearable powered robot during stroke rehabilitation: a randomized parallel-group trial.

Miyagawa, Daichi / Matsushima, Akira / Maruyama, Yoichi / Mizukami, Noriaki / Tetsuya, Mikio / Hashimoto, Minoru / Yoshida, Kunihiro

Journal of neuroengineering and rehabilitation

2023 Volume 20, Issue 1, Page(s) 54

Abstract: Background: We have developed a wearable rehabilitation robot, "curara®," and examined its immediate effect in patients with spinocerebellar degeneration and stroke, but its rehabilitative effect has not been clarified. The purpose of this study was to ... ...

Abstract	Background: We have developed a wearable rehabilitation robot, "curara®," and examined its immediate effect in patients with spinocerebellar degeneration and stroke, but its rehabilitative effect has not been clarified. The purpose of this study was to examine the effect of this device on gait training in stroke patients. Methods: Forty stroke patients were enrolled in this study. The participants were divided randomly into two groups (groups A and B). The participants assigned to group A received RAGT with curara® type 4, whereas those in group B received conventional therapist-assisted gait training. The clinical trial period was 15 days. The participants performed 10 sessions of gait training (5 times per week) each lasting 30 ± 5 min per day. The 10-m walking time (10mWT), and 6-minute walking distance (6MWD) were evaluated as the main outcomes. Timed up and go and Berg Balance Scale (BBS) were also examined. Gait parameters (stride duration and length, standard deviation of stride duration and length, cadence, ratio of the stance/swing phases, minimum/maximum knee joint angle, and minimum/maximum hip joint angle) were measured using a RehaGait®. The items other than BBS were measured on days 0, 7, and 14, whereas BBS was measured on days 0 and 14. The improvement rate was calculated as the difference of values between days 14 and 0 divided by the value on day 0. The improvement rates of the 10mWT and 6MWD were set as the main outcomes. Results: The data of 35 participants were analyzed. There was no significant difference in the main outcomes between both groups at the end of gait training. As for intragroup changes, gait speed, stride length, stride duration, and cadence were improved significantly between days 0 and 14 in each group. When examining the interaction effect between the day of measurement and group, stride duration (p = 0.006) and cadence (p = 0.012) were more significantly improved in group A than in group B. Conclusions: This novel wearable powered robot may have the potential to improve gait speed of individuals in stroke rehabilitation. Trial registration: Japan Registry of Clinical Trials (jRCTs032180163). Registered on February 22, 2019; https://jrct.niph.go.jp/en-latest-detail/jRCTs032180163 . UMIN CLINICAL TRIALS REGISTRY (UMIN000034237): Registered on September 22, 2018; https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000038939 .
MeSH term(s)	Humans ; Stroke Rehabilitation ; Robotics ; Gait ; Stroke ; Wearable Electronic Devices ; Gait Disorders, Neurologic/etiology ; Gait Disorders, Neurologic/rehabilitation ; Treatment Outcome
Language	English
Publishing date	2023-04-28
Publishing country	England
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2164377-5
ISSN	1743-0003 ; 1743-0003
ISSN (online)	1743-0003
ISSN	1743-0003
DOI	10.1186/s12984-023-01168-x
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Article ; Online: An elemental diet protects mouse salivary glands from 5-fluorouracil-induced atrophy.

Harada, Koji / Ferdous, Tarannum / Fujiwara, Rieko / Watanabe, Kenji / Mizukami, Yoichi / Mishima, Katsuaki

Oncology letters

2022 Volume 23, Issue 6, Page(s) 178

Abstract: An elemental diet (ED) reduces adverse effects of chemotherapy, including oral mucositis, in patients with cancer. However, the detailed mechanism(s) of the healing effects of an ED remains unclear. In the present study, the protective effects of the ED, ...

Abstract	An elemental diet (ED) reduces adverse effects of chemotherapy, including oral mucositis, in patients with cancer. However, the detailed mechanism(s) of the healing effects of an ED remains unclear. In the present study, the protective effects of the ED, Elental
Language	English
Publishing date	2022-04-14
Publishing country	Greece
Document type	Journal Article
ZDB-ID	2573196-8
ISSN	1792-1082 ; 1792-1074
ISSN (online)	1792-1082
ISSN	1792-1074
DOI	10.3892/ol.2022.13298
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Article: Elemental diet directly affects chemotherapy-induced dermatitis and raw wound areas.

Harada, Koji / Takenawa, Takanori / Ferdous, Tarannum / Mizukami, Yoichi / Mishima, Katsuaki

Molecular and clinical oncology

2020 Volume 13, Issue 2, Page(s) 209–215

Abstract: ... ...

Abstract	Elental
Language	English
Publishing date	2020-05-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2796865-0
ISSN	2049-9469 ; 2049-9450
ISSN (online)	2049-9469
ISSN	2049-9450
DOI	10.3892/mco.2020.2050
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Article ; Online: Hydrogen sulfide suppresses the proliferation of intestinal epithelial cells through cell cycle arrest.

Xu, Wenxi / Watanabe, Kenji / Mizukami, Yoichi / Yamamoto, Yoshinari / Suzuki, Takuya

Archives of biochemistry and biophysics

2021 Volume 712, Page(s) 109044

Abstract: The pathogenesis of chronic kidney disease (CKD) is closely related to the changes in the intestinal microbiota and integrity. Our previous studies have shown the accumulation of hydrogen sulfide ( ... ...

Abstract	The pathogenesis of chronic kidney disease (CKD) is closely related to the changes in the intestinal microbiota and integrity. Our previous studies have shown the accumulation of hydrogen sulfide (H
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Epithelial Cells/drug effects ; G2 Phase Cell Cycle Checkpoints/drug effects ; Gene Expression Regulation/drug effects ; Humans ; Hydrogen Sulfide/pharmacology ; Intestines/cytology ; MAP Kinase Signaling System/drug effects ; Morpholines/pharmacology ; Organothiophosphorus Compounds/pharmacology ; Rats
Chemical Substances	GYY 4137 ; Morpholines ; Organothiophosphorus Compounds ; Hydrogen Sulfide (YY9FVM7NSN)
Language	English
Publishing date	2021-09-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2021.109044
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Article ; Online: Anti-inflammatory effects of differential molecular weight Hyaluronic acids on UVB-induced calprotectin-mediated keratinocyte inflammation.

Hu, Liuying / Nomura, Satoshi / Sato, Yasunari / Takagi, Kyoko / Ishii, Tsuyoshi / Honma, Yoichi / Watanabe, Kenji / Mizukami, Yoichi / Muto, Jun

Journal of dermatological science

2022 Volume 107, Issue 1, Page(s) 24–31

Abstract: Background: The biological functions of Hyaluronic acid are related to its molecular weight and binding to its receptor, Toll-like receptor4 (TLR4) or CD44. Recent studies have shown that low-molecular-weight Hyaluronic acid (LMW-HA) exhibits ... ...

Abstract	Background: The biological functions of Hyaluronic acid are related to its molecular weight and binding to its receptor, Toll-like receptor4 (TLR4) or CD44. Recent studies have shown that low-molecular-weight Hyaluronic acid (LMW-HA) exhibits proinflammatory effects, while high-molecular-weight Hyaluronic acid (HMW-HA) functions as an anti-inflammatory factor. UVB-induced epidermal inflammation is mainly mediated by endogenous molecules, such as damage-associated molecular patterns (DAMPs), that cause severe skin damage by activating TLR signaling pathways. Objective: Since both LMW- and HMW-HA have inhibitory functions on TLR-mediated macrophage inflammation, HA is assumed to suppress UVB-induced DAMP-mediated inflammation in the skin. In this study, both Ultra- low-molecular-weight Hyaluronic acid (uLMW-HA) and HMW-HA were found to inhibit UVB-induced keratinocyte inflammation. Methods: HaCaT cells were treated with medium containing Hyaluronic acid at the appropriate concentration after 15 mJ/cm Results: By competitively binding to TLR4, uLMW-HA downregulated Calprotectin-induced TRAF6 expression, which might be the direct process by which uLMW-HA decreased UVB-induced IL-6 secretion. Reduced　CD44 variant (CD44v) expression in keratinocytes attenuated the inhibitory effect of both uLMW-HA and HMW-HA on UVB-induced inflammation, which indicated the involvement of CD44v in HA-regulated anti-inflammatory activity. Conclusion: Overall, this research indicates that Hyaluronic acid is more than a moisturizer; it is also a biologically effective material that can prevent the excessive skin inflammation caused in daily life, especially in the late stages after sunburn.
MeSH term(s)	Anti-Inflammatory Agents ; Humans ; Hyaluronic Acid ; Inflammation ; Keratinocytes ; Leukocyte L1 Antigen Complex ; Molecular Weight ; Toll-Like Receptor 4
Chemical Substances	Anti-Inflammatory Agents ; Leukocyte L1 Antigen Complex ; Toll-Like Receptor 4 ; Hyaluronic Acid (9004-61-9)
Language	English
Publishing date	2022-06-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1024446-3
ISSN	1873-569X ; 0923-1811
ISSN (online)	1873-569X
ISSN	0923-1811
DOI	10.1016/j.jdermsci.2022.06.001
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Article ; Online: The effect of 5-aminolevulinic acid on canine peripheral blood mononuclear cells.

Igase, Masaya / Iwatani, Nao / Sakai, Aki / Watanabe, Kenji / Mizukami, Yoichi / Mizuno, Takuya

Veterinary immunology and immunopathology

2022 Volume 251, Page(s) 110473

Abstract: 5-aminolevulinic acid (ALA) is a natural amino acid and a product of the first heme synthesis pathway in mitochondria. Its immunomodulatory effects have garnered recent attention for their potential application to cancer, inflammation, and autoimmune ... ...

Abstract	5-aminolevulinic acid (ALA) is a natural amino acid and a product of the first heme synthesis pathway in mitochondria. Its immunomodulatory effects have garnered recent attention for their potential application to cancer, inflammation, and autoimmune diseases in humans. A supplement containing ALA is now available in Japan to enhance ATP synthesis via mitochondrial activity. However, how ALA affects canine immunity is unclear. Here we studied the effects of ALA on peripheral blood mononuclear cells (PBMCs) from healthy dogs in vitro. Heme oxygenase-1 (HO-1) protein was expressed in Madin-Darby canine kidney (MDCK) cells and PBMCs treated with ALA and ferrous sodium citrate (SFC), which showed that ALA works in dogs as well as humans. ALA also induced concanavalin A (ConA)-stimulated PBMCs to produce significantly more interferon-gamma (IFN-γ). Next-generation RNA sequencing (RNA-seq) revealed that ALA enhanced T cell immunity among Th1, Th2, and Th17 subsets, especially the IL-17 signaling pathway. We then confirmed that ALA promoted interleukin (IL)- 17A production in ConA-stimulated PBMCs. Together, these findings indicate that ALA promotes heme synthesis in mitochondria and enhances ConA-induced T cell immune responses in canine PBMCs.
MeSH term(s)	Aminolevulinic Acid/pharmacology ; Animals ; Dog Diseases ; Dogs ; Heme ; Humans ; Inflammation/metabolism ; Inflammation/veterinary ; Leukocytes, Mononuclear ; Signal Transduction
Chemical Substances	Heme (42VZT0U6YR) ; Aminolevulinic Acid (88755TAZ87)
Language	English
Publishing date	2022-08-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	754160-0
ISSN	1873-2534 ; 0165-2427
ISSN (online)	1873-2534
ISSN	0165-2427
DOI	10.1016/j.vetimm.2022.110473
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