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Article ; Online: Peripheral itch sensitization in atopic dermatitis.

Tominaga, Mitsutoshi / Takamori, Kenji

Allergology international : official journal of the Japanese Society of Allergology

2022 Volume 71, Issue 3, Page(s) 265–277

Abstract: Atopic dermatitis is a skin disorder caused by skin dryness and barrier dysfunction, resulting in skin inflammation and chronic itch (or pruritus). The pathogenesis of atopic dermatitis is thought to be initiated by a lowering of the itch threshold due ... ...

Abstract	Atopic dermatitis is a skin disorder caused by skin dryness and barrier dysfunction, resulting in skin inflammation and chronic itch (or pruritus). The pathogenesis of atopic dermatitis is thought to be initiated by a lowering of the itch threshold due to dry skin. This lowering of the itch threshold is at least partially due to the increase in intraepidermal nerve fibers and sensitization of sensory nerves by interleukin (IL)-33 produced and secreted by keratinocytes. Such skin is easily prone to itch due to mechanical stimuli, such as rubbing of clothing and chemical stimuli from itch mediators. In patients with atopic dermatitis, once itch occurs, further itch is induced by scratching, and the associated scratching breaks down the skin barrier. Disruption of the skin barrier allows entry into the epidermis of external foreign substances, such as allergens derived from house dust mites, leading to an increased induction of type 2 inflammatory responses. As a result, type 2 cytokines IL-4, IL-13, and IL-31 are mainly secreted by Th2 cells, and their action on sensory nerve fibers causes further itch sensitization. These sequences of events are thought to occur simultaneously in patients with atopic dermatitis, leading to a vicious itch-scratch cycle. This vicious cycle becomes a negative spiral that leads to disease burden. Therefore, controlling itch is essential for the treatment of atopic dermatitis. In this review, we summarize and discuss advances in the mechanisms of peripheral itch sensitization in atopic dermatitis, focusing on skin barrier-neuro-immune triadic connectivity.
MeSH term(s)	Allergens ; Cytokines ; Dermatitis, Atopic ; Epidermis/pathology ; Humans ; Pruritus/etiology ; Pruritus/pathology ; Skin/pathology
Chemical Substances	Allergens ; Cytokines
Language	English
Publishing date	2022-05-25
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1336498-4
ISSN	1440-1592 ; 1323-8930
ISSN (online)	1440-1592
ISSN	1323-8930
DOI	10.1016/j.alit.2022.04.003
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Article ; Online: Virus-prokaryote infection pairs associated with prokaryotic production in a freshwater lake.

Shen, Shang / Tominaga, Kento / Tsuchiya, Kenji / Matsuda, Tomonari / Yoshida, Takashi / Shimizu, Yoshihisa

mSystems

2024 Volume 9, Issue 2, Page(s) e0090623

Abstract: Viruses infect and kill prokaryotic populations in a density- or frequency-dependent manner and affect carbon cycling. However, the effects of the stratification transition, including the stratified and de-stratified periods, on the changes in ... ...

Abstract	Viruses infect and kill prokaryotic populations in a density- or frequency-dependent manner and affect carbon cycling. However, the effects of the stratification transition, including the stratified and de-stratified periods, on the changes in prokaryotic and viral communities and their interactions remain unclear. We conducted a monthly survey of the surface and deep layers of a large and deep freshwater lake (Lake Biwa, Japan) for a year and analyzed the prokaryotic production and prokaryotic and viral community composition. Our analysis revealed that, in the surface layer, 19 prokaryotic species, accounting for approximately 40% of the total prokaryotic abundance, could potentially contribute to the majority of prokaryotic production, which is the highest during the summer and is suppressed by viruses. This suggests that a small fraction of prokaryotes and phages were the key infection pairs during the peak period of prokaryotic activity in the freshwater lake. We also found that approximately 50% of the dominant prokaryotic and viral species in the deep layer were present throughout the study period. This suggests that the "kill the winner" model could explain the viral impact on prokaryotes in the surface layer, but other dynamics may be at play in the deep layer. Furthermore, we found that annual vertical mixing could result in a similar rate of community change between the surface and deep layers. These findings may be valuable in understanding how communities and the interaction among them change when freshwater lake stratification is affected by global warming in the future.IMPORTANCEViral infection associated with prokaryotic production occurs in a density- or frequency-dependent manner and regulates the prokaryotic community. Stratification transition and annual vertical mixing in freshwater lakes are known to affect the prokaryotic community and the interaction between prokaryotes and viruses. By pairing measurements of virome analysis and prokaryotic production of a 1-year survey of the depths of surface and deep layers, we revealed (i) the prokaryotic infection pairs associated with prokaryotic production and (ii) the reset in prokaryotic and viral communities through annual vertical mixing in a freshwater lake. Our results provide a basis for future work into changes in stratification that may impact the biogeochemical cycling in freshwater lakes.
MeSH term(s)	Lakes/chemistry ; Prokaryotic Cells ; Viruses/genetics ; Bacteriophages/genetics ; Japan
Language	English
Publishing date	2024-01-09
Publishing country	United States
Document type	Journal Article
ISSN	2379-5077
ISSN (online)	2379-5077
DOI	10.1128/msystems.00906-23
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Article ; Online: An Altered Skin and Gut Microbiota Are Involved in the Modulation of Itch in Atopic Dermatitis.

Moniaga, Catharina Sagita / Tominaga, Mitsutoshi / Takamori, Kenji

Cells

2022 Volume 11, Issue 23

Abstract: Skin and gut microbiota play an important role in the pathogenesis of atopic dermatitis (AD). An alteration of the microbiota diversity modulates the development and course of AD, e.g., decreased microbiome diversity correlates with disease severity, ... ...

Abstract	Skin and gut microbiota play an important role in the pathogenesis of atopic dermatitis (AD). An alteration of the microbiota diversity modulates the development and course of AD, e.g., decreased microbiome diversity correlates with disease severity, particularly in lesional skin of AD. Itch is a hallmark of AD with unsatisfying treatment until now. Recent evidence suggests a possible role of microbiota in altering itch in AD through gut-skin-brain interactions. The microbial metabolites, proinflammatory cytokines, and impaired immune response lead to a modulation of histamine-independent itch, disruption of epidermal barrier, and central sensitization of itch mechanisms. The positive impact of probiotics in alleviating itch in AD supports this hypothesis, which may lead to novel strategies for managing itchy skin in AD patients. This review summarizes the emerging findings on the correlation between an altered microbiota and gut-skin-brain axis in AD, especially in modulating itchy skin.
Language	English
Publishing date	2022-12-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11233930
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Article: Treatment Options for Troublesome Itch.

Toyama, Sumika / Tominaga, Mitsutoshi / Takamori, Kenji

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 8

Abstract: Itch (or pruritus) is an unpleasant sensation, inducing the desire to scratch. It is also a major and distressing symptom of many skin and systemic diseases. The involvement of histamine, which is a major itch mediator, has been extensively examined. ... ...

Abstract	Itch (or pruritus) is an unpleasant sensation, inducing the desire to scratch. It is also a major and distressing symptom of many skin and systemic diseases. The involvement of histamine, which is a major itch mediator, has been extensively examined. Recent studies suggest that histamine-independent pathways may play roles in chronic itch. Therefore, antihistamines are not always effective in the treatment of patients with chronic itch. The development of biologics and κ-opioid receptor (KOR) agonists has contributed to advances in the treatment of itch; however, since biologics are expensive for patients to purchase, some patients may limit or discontinue their use of these agents. Furthermore, KOR agonists need to be prescribed with caution due to risks of side effects in the central nervous system. Janus kinase (JAK) inhibitors are sometimes associated with side effects, such as infection. In this review, we summarize antidepressants, antineuralgics, cyclosporine A, antibiotics, crotamiton, phosphodiesterase 4 inhibitor, botulinum toxin type A, herbal medicines, phototherapy, and acupuncture therapy as itch treatment options other than antihistamines, biologics, opioids, and JAK inhibitors; we also explain their underlying mechanisms of action.
Language	English
Publishing date	2022-08-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15081022
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Article ; Online: An Altered Skin and Gut Microbiota Are Involved in the Modulation of Itch in Atopic Dermatitis

Catharina Sagita Moniaga / Mitsutoshi Tominaga / Kenji Takamori

Cells, Vol 11, Iss 3930, p

2022 Volume 3930

Abstract	Skin and gut microbiota play an important role in the pathogenesis of atopic dermatitis (AD). An alteration of the microbiota diversity modulates the development and course of AD, e.g., decreased microbiome diversity correlates with disease severity, particularly in lesional skin of AD. Itch is a hallmark of AD with unsatisfying treatment until now. Recent evidence suggests a possible role of microbiota in altering itch in AD through gut–skin–brain interactions. The microbial metabolites, proinflammatory cytokines, and impaired immune response lead to a modulation of histamine-independent itch, disruption of epidermal barrier, and central sensitization of itch mechanisms. The positive impact of probiotics in alleviating itch in AD supports this hypothesis, which may lead to novel strategies for managing itchy skin in AD patients. This review summarizes the emerging findings on the correlation between an altered microbiota and gut–skin–brain axis in AD, especially in modulating itchy skin.
Keywords	skin ; gut ; microbiota ; itch ; atopic dermatitis ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Short-term outcomes after laparoscopic colorectal cancer surgery in patients over 90 years old: a Japanese multicenter study.

Yamashita, Mariko / Tominaga, Tetsuro / Nonaka, Takashi / Hisanaga, Makoto / Takeshita, Hiroaki / Fukuoka, Hidetoshi / To, Kazuo / Tanaka, Kenji / Sawai, Terumitsu / Nagayasu, Takeshi

BMC surgery

2024 Volume 24, Issue 1, Page(s) 2

Abstract: Background: The effect of laparoscopic surgery on short-term outcomes in colorectal cancer patients over 90 years old has remained unclear.: Methods: We reviewed 87 colorectal cancer patients aged over 90 years who underwent surgery between 2016 and ... ...

Abstract	Background: The effect of laparoscopic surgery on short-term outcomes in colorectal cancer patients over 90 years old has remained unclear. Methods: We reviewed 87 colorectal cancer patients aged over 90 years who underwent surgery between 2016 and 2022. Patients were divided into an open surgery group (n = 22) and a laparoscopic surgery group (n = 65). The aim of this study was to investigate the effect of laparoscopic surgery on postoperative outcome in elderly colorectal cancer patients, as compared to open surgery. Results: Seventy-eight patients (89.7%) had comorbidities. Frequency of advanced T stage was lower with laparoscopic surgery (p = 0.021). Operation time was longer (open surgery 146 min vs. laparoscopic surgery 203 min; p = 0.002) and blood loss was less (105 mL vs. 20 mL, respectively; p < 0.001) with laparoscopic surgery. Length of hospitalization was longer with open surgery (22 days vs. 18 days, respectively; p = 0.007). Frequency of infectious complications was lower with laparoscopic surgery (18.5%) than with open surgery (45.5%; p = 0.021). Multivariate analysis revealed open surgery (p = 0.026; odds ratio, 3.535; 95% confidence interval, 1.159-10.781) as an independent predictor of postoperative infectious complications. Conclusions: Laparoscopic colorectal resection for patients over 90 years old is a useful procedure that reduces postoperative infectious complications.
MeSH term(s)	Aged, 80 and over ; Humans ; Colectomy/adverse effects ; Colectomy/methods ; Colorectal Neoplasms/surgery ; Japan/epidemiology ; Laparoscopy/adverse effects ; Laparoscopy/methods ; Postoperative Complications/epidemiology ; Retrospective Studies ; Treatment Outcome
Language	English
Publishing date	2024-01-02
Publishing country	England
Document type	Journal Article ; Multicenter Study
ZDB-ID	2050442-1
ISSN	1471-2482 ; 1471-2482
ISSN (online)	1471-2482
ISSN	1471-2482
DOI	10.1186/s12893-023-02298-8
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Article ; Online: Effects of Psychological Stress on Spontaneous Itch and Mechanical Alloknesis of Atopic Dermatitis.

Zhao, Qiaofeng / Tominaga, Mitsutoshi / Toyama, Sumika / Komiya, Eriko / Tobita, Tomohiro / Morita, Motoki / Zuo, Ying / Honda, Kotaro / Kamata, Yayoi / Takamori, Kenji

Acta dermato-venereologica

2024 Volume 104, Page(s) adv18685

Abstract: Atopic dermatitis (AD), a chronic inflammatory skin disease, manifests as an intractable itch. Psychological stress has been suggested to play a role in the onset and worsening of AD symptoms. However, the pathophysiological relationships between ... ...

Abstract	Atopic dermatitis (AD), a chronic inflammatory skin disease, manifests as an intractable itch. Psychological stress has been suggested to play a role in the onset and worsening of AD symptoms. However, the pathophysiological relationships between psychological stressors and cutaneous manifestations remain unclear. To elucidate the mechanisms underlying the stress-related exacerbation of itch, we investigated the effects of water stress, restraint stress and repeated social defeat stress on itch-related scratching behaviour, mechanical alloknesis and dermatitis in male NC/Nga mice with AD-like symptoms induced by the repeated application of ointment containing Dermatophagoides farina body. NC/Nga mice with AD-like symptoms were subjected to water stress, restraint stress and repeated social defeat stress, and their scratching behaviour, sensitivity to mechanical stimuli (mechanical alloknesis) and severity of dermatitis were evaluated. Social defeat stress+ Dermatophagoides farina body-treated mice exposed to stress showed slower improvements in or the exacerbation of AD-like symptoms, including dermatitis and itch. In the mechanical alloknesis assay, the mechanical alloknesis scores of social defeat stress+ Dermatophagoides farina body-treated mice exposed to stress were significantly higher than those of non-exposed social defeat stress+ Dermatophagoides farina body- and social defeat stress-treated mice. These results suggest that psychological stress delays improvements in dermatitis by exacerbating itch hypersensitivity in AD.
MeSH term(s)	Male ; Mice ; Animals ; Dermatitis, Atopic ; Dehydration ; Pruritus/etiology ; Skin ; Stress, Psychological/complications ; Disease Models, Animal
Language	English
Publishing date	2024-04-02
Publishing country	Sweden
Document type	Journal Article
ZDB-ID	80007-7
ISSN	1651-2057 ; 0001-5555
ISSN (online)	1651-2057
ISSN	0001-5555
DOI	10.2340/actadv.v104.18685
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Article ; Online: Identification of Keratinocyte Cytoprotectants against Toxicity by the Multikinase Inhibitor Sorafenib Using Drug Repositioning.

Kamata, Yayoi / Kato, Rui / Tominaga, Mitsutoshi / Toyama, Sumika / Komiya, Eriko / Utsumi, Jun / Kaneko, Takahide / Suga, Yasushi / Takamori, Kenji

JID innovations : skin science from molecules to population health

2024 Volume 4, Issue 3, Page(s) 100271

Abstract: Hand-foot skin reaction is the most common adverse event of multikinase inhibitors, such as sorafenib. Although hand-foot skin reaction is not life threatening, severe cases impair quality of life because of pain and reduced activities of daily living. ... ...

Abstract	Hand-foot skin reaction is the most common adverse event of multikinase inhibitors, such as sorafenib. Although hand-foot skin reaction is not life threatening, severe cases impair quality of life because of pain and reduced activities of daily living. However, the pathological mechanisms of hand-foot skin reaction have not yet been elucidated in detail, and there is currently no effective treatment. We aimed to identify keratinocyte cytoprotectants against sorafenib toxicity. The screening of cytoprotectants against sorafenib toxicity was performed using cultured normal human epidermal keratinocytes or a reconstructed human epidermis model and off-patent approved drugs in the Prestwick Chemical library. Among 1273 drugs in the chemical library, 8 dose-dependently increased cell viability by >200% in the presence of sorafenib. In the presence of sorafenib, the number of proliferating cell nuclear antigen-positive cells was significantly higher in clofazimine-, cyclosporin A-, and itraconazole-treated reconstructed human epidermis models than in sorafenib-treated models, and candidate drugs suppressed sorafenib-induced apoptosis in normal human epidermal keratinocytes. In addition, clofazimine, itraconazole, and pyrvinium pamoate significantly recovered the phosphorylation of extracellular signal-regulated kinase 1/2 in the presence of sorafenib. Collectively, hit drugs promoted cell viability and normalized keratinocyte proliferation in the presence of sorafenib. These candidate drugs have potential as treatments for multikinase inhibitor-induced hand-foot skin reaction.
Language	English
Publishing date	2024-02-28
Publishing country	Netherlands
Document type	Journal Article
ISSN	2667-0267
ISSN (online)	2667-0267
DOI	10.1016/j.xjidi.2024.100271
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Article: The Pathology of Type 2 Inflammation-Associated Itch in Atopic Dermatitis.

Moniaga, Catharina Sagita / Tominaga, Mitsutoshi / Takamori, Kenji

Diagnostics (Basel, Switzerland)

2021 Volume 11, Issue 11

Abstract: Accumulated evidence on type 2 inflammation-associated itch in atopic dermatitis has recently been reported. Crosstalk between the immune and nervous systems (neuroimmune interactions) is prominent in atopic dermatitis research, particularly regarding ... ...

Abstract	Accumulated evidence on type 2 inflammation-associated itch in atopic dermatitis has recently been reported. Crosstalk between the immune and nervous systems (neuroimmune interactions) is prominent in atopic dermatitis research, particularly regarding itch and inflammation. A comprehensive understanding of bidirectional neuroimmune interactions will provide insights into the pathogenesis of itch and its treatment. There is currently no agreed cure for itch in atopic dermatitis; however, increasing numbers of novel and targeted biologic agents have potential for its management and are in the advanced stages of clinical trials. In this review, we summarize and discuss advances in our understanding of type 2 inflammation-associated itch and implications for its management and treatment in patients with atopic dermatitis.
Language	English
Publishing date	2021-11-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics11112090
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Article ; Online: Tip60/KAT5 Histone Acetyltransferase Is Required for Maintenance and Neurogenesis of Embryonic Neural Stem Cells.

Tominaga, Kaoru / Sakashita, Eiji / Kasashima, Katsumi / Kuroiwa, Kenji / Nagao, Yasumitsu / Iwamori, Naoki / Endo, Hitoshi

International journal of molecular sciences

2023 Volume 24, Issue 3

Abstract: Epigenetic regulation via epigenetic factors in collaboration with tissue-specific transcription factors is curtail for establishing functional organ systems during development. Brain development is tightly regulated by epigenetic factors, which are ... ...

Abstract	Epigenetic regulation via epigenetic factors in collaboration with tissue-specific transcription factors is curtail for establishing functional organ systems during development. Brain development is tightly regulated by epigenetic factors, which are coordinately activated or inactivated during processes, and their dysregulation is linked to brain abnormalities and intellectual disability. However, the precise mechanism of epigenetic regulation in brain development and neurogenesis remains largely unknown. Here, we show that Tip60/KAT5 deletion in neural stem/progenitor cells (NSCs) in mice results in multiple abnormalities of brain development. Tip60-deficient embryonic brain led to microcephaly, and proliferating cells in the developing brain were reduced by Tip60 deficiency. In addition, neural differentiation and neuronal migration were severely affected in Tip60-deficient brains. Following neurogenesis in developing brains, gliogenesis started from the earlier stage of development in Tip60-deficient brains, indicating that Tip60 is involved in switching from neurogenesis to gliogenesis during brain development. It was also confirmed in vitro that poor neurosphere formation, proliferation defects, neural differentiation defects, and accelerated astrocytic differentiation in mutant NSCs are derived from Tip60-deficient embryonic brains. This study uncovers the critical role of Tip60 in brain development and NSC maintenance and function in vivo and in vitro.
MeSH term(s)	Mice ; Animals ; Histone Acetyltransferases/genetics ; Epigenesis, Genetic ; Neurogenesis ; Neural Stem Cells ; Embryonic Stem Cells ; Cell Differentiation/physiology
Chemical Substances	Histone Acetyltransferases (EC 2.3.1.48)
Language	English
Publishing date	2023-01-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24032113
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