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Article ; Online: The Role of Cysteine Protease Cathepsins B, H, C, and X/Z in Neurodegenerative Diseases and Cancer

Veronika Stoka / Olga Vasiljeva / Hiroshi Nakanishi / Vito Turk

International Journal of Molecular Sciences, Vol 24, Iss 21, p

2023 Volume 15613

Abstract: Papain-like cysteine proteases are composed of 11 human cysteine cathepsins, originally located in the lysosomes. They exhibit broad specificity and act as endopeptidases and/or exopeptidases. Among them, only cathepsins B, H, C, and X/Z exhibit ... ...

Abstract	Papain-like cysteine proteases are composed of 11 human cysteine cathepsins, originally located in the lysosomes. They exhibit broad specificity and act as endopeptidases and/or exopeptidases. Among them, only cathepsins B, H, C, and X/Z exhibit exopeptidase activity. Recently, cysteine cathepsins have been found to be present outside the lysosomes and often participate in various pathological processes. Hence, they have been considered key signalling molecules. Their potentially hazardous proteolytic activities are tightly regulated. This review aims to discuss recent advances in understanding the structural aspects of these four cathepsins, mechanisms of their zymogen activation, regulation of their activities, and functional aspects of these enzymes in neurodegeneration and cancer. Neurodegenerative effects have been evaluated, particularly in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and neuropsychiatric disorders. Cysteine cathepsins also participate in tumour progression and metastasis through the overexpression and secretion of proteases, which trigger extracellular matrix degradation. To our knowledge, this is the first review to provide an in-depth analysis regarding the roles of cysteine cathepsins B, H, C, and X in neurodegenerative diseases and cancer. Further advances in understanding the functions of cysteine cathepsins in these conditions will result in the development of novel, targeted therapeutic strategies.
Keywords	cathepsins ; lysosomal exopeptidases ; neurodegeneration ; Alzheimer’s disease ; Parkinson’s disease ; Huntington’s disease ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610 ; 572
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Human β-Defensin 3 Inhibits Porphyromonas Gingivalis Lipopolysaccharide-Induced Oxidative and Inflammatory Responses of Microglia by Suppression of Cathepsins B and L

Erika Inoue / Shiyo Minatozaki / Yui Katsuta / Saori Nonaka / Hiroshi Nakanishi

International Journal of Molecular Sciences, Vol 23, Iss 15099, p

2022 Volume 15099

Abstract: Recently, the effects of antibacterial peptides are suggested to have therapeutic potential in Alzheimer’s disease. Furthermore, systemic treatment of Porphyromonas gingivalis ( Pg ) lipopolysaccharide (LPS) induced Alzheimer’s disease-like ... ...

Abstract	Recently, the effects of antibacterial peptides are suggested to have therapeutic potential in Alzheimer’s disease. Furthermore, systemic treatment of Porphyromonas gingivalis ( Pg ) lipopolysaccharide (LPS) induced Alzheimer’s disease-like neuropathological changes in middle-aged mice. Then, we examined whether human β-defensins (hBDs), antimicrobial peptides produced by the oral mucosa and salivary glands, can suppress Pg LPS-induced oxidative and inflammatory responses by microglia. hBD3 (1 μM) significantly suppressed Pg LPS-induced production of nitric oxide and interleukin-6 (IL-6) by MG6 cells, a mouse microglial cell line. hBD3 (1 μM) also significantly inhibited Pg LPS-induced expression of IL-6 by HMC3 cells, a human microglial cell line. In contrast, neither hBD1, hBD2 nor hBD4 failed to inhibit their productions. Furthermore, hBD3 suppressed Pg LPS-induced p65 nuclear translocation through the IκBα degradation. Pg LPS-induced expression of IL-6 was significantly suppressed by E64d, a cysteine protease inhibitor, and CA-074Me, a known specific inhibitor for cathepsin B, but not by pepstatin A, an aspartic protease inhibitor. Interestingly, hBD3 significantly inhibited enzymatic activities of recombinant human cathepsins B and L, lysosomal cysteine proteases, and their intracellular activities in MG6 cells. Therefore, hBD3 suppressed oxidative and inflammatory responses of microglia through the inhibition of cathepsins B and L, which enzymatic activities are necessary for the NF-κB activation.
Keywords	antibacterial peptide ; cathepsin B ; cathepsin L ; human β-defensins ; interleukin-6 ; lipopolysaccharide ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
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: ATP13A2 modifies mitochondrial localization of overexpressed TOM20 to autolysosomal pathway

Yuta Hatori / Yukina Kanda / Saori Nonaka / Hiroshi Nakanishi / Takeo Kitazawa

PLoS ONE, Vol 17, Iss

2022 Volume 11

Abstract: Mutations in ATP13A2 cause Kufor-Rakeb Syndrome (KRS), a juvenile form of Parkinson’s Disease (PD). The gene product belongs to a diverse family of ion pumps and mediates polyamine influx from lysosomal lumen. While the biochemical and structural studies ...

Abstract	Mutations in ATP13A2 cause Kufor-Rakeb Syndrome (KRS), a juvenile form of Parkinson’s Disease (PD). The gene product belongs to a diverse family of ion pumps and mediates polyamine influx from lysosomal lumen. While the biochemical and structural studies highlight its unique mechanics, how PD pathology is linked to ATP13A2 function remains unclear. Here we report that localization of overexpressed TOM20, a mitochondrial outer-membrane protein, is significantly altered upon ATP13A2 expression to partially merge with lysosome. Using Halo-fused version of ATP13A2, ATP13A2 was identified in lysosome and autophagosome. Upon ATP13A2 co-expression, overexpressed TOM20 was found not only in mitochondria but also within ATP13A2-containing autolysosome. This modification of TOM20 localization was inhibited by adding 1-methyl-4-phenylpyridinium (MPP+) and not accompanied with mitophagy induction. We suggest that ATP13A2 may participate in the control of overexpressed proteins targeted to mitochondrial outer-membrane.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Stem cells from human exfoliated deciduous teeth attenuate mechanical allodynia in mice through distinct from the siglec-9/MCP-1-mediated tissue-repairing mechanism

Yoshinori Hayashi / Hiroki Kato / Kazuaki Nonaka / Hiroshi Nakanishi

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 10

Abstract: Abstract The effects of stem cells from human exfoliated deciduous teeth (SHED) on mechanical allodynia were examined in mice. A single intravenous injection of SHED and conditioned medium from SHED (SHED-CM) through the left external jugular vein ... ...

Abstract	Abstract The effects of stem cells from human exfoliated deciduous teeth (SHED) on mechanical allodynia were examined in mice. A single intravenous injection of SHED and conditioned medium from SHED (SHED-CM) through the left external jugular vein significantly reversed the established mechanical allodynia induced by spinal nerve transection at 6 days after injection. SHED or SHED-CM significantly decreased the mean numbers of activating transcription factor 3-positive neurons and macrophages in the ipsilateral side of the dorsal root ganglion (DRG) at 20 days after spinal nerve transection. SHED or SHED-CM also suppressed activation of microglia and astrocytes in the ipsilateral side of the dorsal spinal cord. A single intravenous injection of secreted ectodomain of sialic acid-binding Ig-like lectin-9 and monocyte chemoattractant protein-1 had no effect on the established mechanical allodynia, whereas a single intravenous injection of protein component(s) contained in SHED-CM with molecular weight of between 30 and 50 kDa reversed the pain. Therefore, it may be concluded that protein component(s) with molecular mass of 30–50 kDa secreted by SHED could protect and/or repair DRG neurons damaged by nerve transection, thereby ameliorating mechanical allodynia.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Generation of CSF1-Independent Ramified Microglia-Like Cells from Leptomeninges In Vitro

Junya Tanaka / Hisaaki Takahashi / Hajime Yano / Hiroshi Nakanishi

Cells, Vol 10, Iss 24, p

2021 Volume 24

Abstract: Although del Río-Hortega originally reported that leptomeningeal cells are the source of ramified microglia in the developing brain, recent views do not seem to pay much attention to this notion. In this study, in vitro experiments were conducted to ... ...

Abstract	Although del Río-Hortega originally reported that leptomeningeal cells are the source of ramified microglia in the developing brain, recent views do not seem to pay much attention to this notion. In this study, in vitro experiments were conducted to determine whether leptomeninges generate ramified microglia. The leptomeninges of neonatal rats containing Iba1 + macrophages were peeled off the brain surface. Leptomeningeal macrophages strongly expressed CD68 and CD163, but microglia in the brain parenchyma did not. Leptomeningeal macrophages expressed epidermal growth factor receptor (EGFR) as revealed by RT-PCR and immunohistochemical staining. Cells obtained from the peeled-off leptomeninges were cultured in a serum-free medium containing EGF, resulting in the formation of large cell aggregates in which many proliferating macrophages were present. In contrast, colony-stimulating factor 1 (CSF1) did not enhance the generation of Iba1 + cells from the leptomeningeal culture. The cell aggregates generated ramified Iba1 + cells in the presence of serum, which express CD68 and CD163 at much lower levels than primary microglia isolated from a mixed glial culture. Therefore, the leptomeningeal-derived cells resembled parenchymal microglia better than primary microglia. This study suggests that microglial progenitors expressing EGFR reside in the leptomeninges and that there is a population of microglia-like cells that grow independently of CSF1.
Keywords	CD68 ; CD163 ; colony-stimulating factor 1 ; epidermal growth factor ; Iba1 ; leptomeninges ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Update on Findings about Sudden Sensorineural Hearing Loss and Insight into Its Pathogenesis

Satoshi Yamada / Junya Kita / Daichi Shinmura / Yuki Nakamura / Sosuke Sahara / Kiyoshi Misawa / Hiroshi Nakanishi

Journal of Clinical Medicine, Vol 11, Iss 6387, p

2022 Volume 6387

Abstract: Sudden sensorineural hearing loss (SSNHL) is routinely encountered and is one of the most common emergent diseases in otolaryngology clinics. However, the etiology of SSNHL remains unclear. Due to the inaccessibility of the living human inner ear for ... ...

Abstract	Sudden sensorineural hearing loss (SSNHL) is routinely encountered and is one of the most common emergent diseases in otolaryngology clinics. However, the etiology of SSNHL remains unclear. Due to the inaccessibility of the living human inner ear for biopsy, studies investigating the etiology of SSNHL have been performed by analyzing data obtained from examinations using peripheral blood or imaging. We updated the findings obtained from serological, magnetic resonance imaging, genetic, and viral examinations to reveal the etiology of SSNHL. Regarding viral examination, we focused on sensorineural hearing loss associated with coronavirus disease (COVID-19) because the number of correlated reports has been increasing after the outbreak. The updated findings revealed the following three possible mechanisms underlying the development of SSNHL: thrombosis and resulting vascular obstruction in the cochlea, asymptomatic viral infection and resulting damage to the cochlea, and cochlear inflammation and resulting damage to the cochlea. Thrombosis and viral infection are predominant, and cochlear inflammation can be secondarily induced through viral infection or even thrombosis. The findings about sensorineural hearing loss associated with COVID-19 supported the possibility that asymptomatic viral infection is one of the etiologies of SSNHL, and the virus can infect inner ear tissues and directly damage them.
Keywords	sudden sensorineural hearing loss ; COVID-19 ; thrombosis ; cochlear inflammation ; viral infection ; SARS-CoV-2 ; Medicine ; R
Subject code	390
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Density Functional Theory-Based Calculation Shed New Light on the Bizarre Addition of Cysteine Thiol to Dopaquinone

Ryo Kishida / Shosuke Ito / Manickam Sugumaran / Ryan Lacdao Arevalo / Hiroshi Nakanishi / Hideaki Kasai

International Journal of Molecular Sciences, Vol 22, Iss 3, p

2021 Volume 1373

Abstract: Two types of melanin pigments, brown to black eumelanin and yellow to reddish brown pheomelanin, are biosynthesized through a branched reaction, which is associated with the key intermediate dopaquinone (DQ). In the presence of l -cysteine, DQ ... ...

Abstract	Two types of melanin pigments, brown to black eumelanin and yellow to reddish brown pheomelanin, are biosynthesized through a branched reaction, which is associated with the key intermediate dopaquinone (DQ). In the presence of l -cysteine, DQ immediately binds to the –SH group, resulting in the formation of cysteinyldopa necessary for the pheomelanin production. l -Cysteine prefers to bond with aromatic carbons adjacent to the carbonyl groups, namely C5 and C2. Surprisingly, this Michael addition takes place at 1,6-position of the C5 (and to some extent at C2) rather than usually expected 1,4-position. Such an anomaly on the reactivity necessitates an atomic-scale understanding of the binding mechanism. Using density functional theory-based calculations, we investigated the binding of l -cysteine thiolate (Cys–S − ) to DQ. Interestingly, the C2–S bonded intermediate was less energetically stable than the C6–S bonded case. Furthermore, the most preferred Cys–S − -attacked intermediate is at the carbon-carbon bridge between the two carbonyls (C3–C4 bridge site) but not on the C5 site. This structure allows the Cys–S − to migrate onto the adjacent C5 or C2 with small activation energies. Further simulation demonstrated a possible conversion pathway of the C5–S (and C2–S) intermediate into 5- S -cysteinyldopa (and 2- S -cysteinyldopa), which is the experimentally identified major (and minor) product. Based on the results, we propose that the binding of Cys–S − to DQ proceeds via the following path: (i) coordination of Cys–S − to C3–C4 bridge, (ii) migration of Cys–S − to C5 (C2), (iii) proton rearrangement from cysteinyl –NH 3 + to O4 (O3), and (iv) proton rearrangement from C5 (C2) to O3 (O4).
Keywords	dopaquinone ; cysteine ; melanin ; density functional theory ; quinone reactions ; thiol addition to quinone ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	333
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Rat Microglia Cells

Dewi Fatma / Hiroshi Nakanishi

Journal of Dentistry Indonesia, Vol 12, Iss 1, Pp 1-

Their Culture, Isolation and Phagocytic Activity

2015 Volume 4

Abstract: Microglia were isolated from mixed primary cell cultures of the cerebral cortex from 3day old male Wistar rats. The mechanically dissociated cells were plated in a flask at a density of 10 7 per 300 cm 2 and maintained at 37°C in a 10% Co 2 /90% air ... ...

Abstract	Microglia were isolated from mixed primary cell cultures of the cerebral cortex from 3day old male Wistar rats. The mechanically dissociated cells were plated in a flask at a density of 10 7 per 300 cm 2 and maintained at 37°C in a 10% Co 2 /90% air atmosphere. After 10-14 days in culture, floating and attached cells on the mixed primary cultured cell layer were isolated by gentle shaking of the flask for 5 min. The resulting cell suspension was transferred to plastic dishes and allowed to adhere at 37°C . To investigate the morphological change of microglia, the cells after 2 days of culture were incubated with biotinylated GSA-1-B4 (10µg/ml) at 4°C for overnight. To detect the phagocytic activity, isolated microglia were incubated with opsonized zymosan (20mgl/ml) for Ih at 37°C and with Giemsa's staining solution for 30 min at room temperature. The results were about 90% of attached cells had amoeboid and rod-shaped cell bodies with no or a few thick processes. Most of these cells became amoeboid-like cells and showed a number of vacuoles in the cytosol when cultured in the presence of IFN-ɣ+LPS. Both control and IFN-ɣ + LPS – treated cells exhibited the intense phagocytic activity against zymosan particles.
Keywords	Microglia cells ; Primary cell cultures ; Phagocytic activity ; Medicine ; R ; Dentistry ; RK1-715
Subject code	571
Language	English
Publishing date	2015-10-01T00:00:00Z
Publisher	University of Indonesia
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Association between human papillomavirus particle production and the severity of recurrent respiratory papillomatosis

Satoshi Yamada / Toshiya Itoh / Taro Ikegami / Atsushi Imai / Daiki Mochizuki / Hiroshi Nakanishi / Ryuji Ishikawa / Junya Kita / Yuki Nakamura / Yoshinori Takizawa / Jun Okamura / Yoshihiro Noda / Toshihide Iwashita / Takahiko Hariyama / Mikio Suzuki / Kiyoshi Misawa / Hideya Kawasaki

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Volume 13

Abstract: Abstract Recurrent respiratory papillomatosis (RRP) has a wide range of severity. We investigate the relationship between human papillomavirus (HPV) particle production and severity of RRP. From September 2005 to June 2021, 68 RRP samples (from 29 ... ...

Abstract	Abstract Recurrent respiratory papillomatosis (RRP) has a wide range of severity. We investigate the relationship between human papillomavirus (HPV) particle production and severity of RRP. From September 2005 to June 2021, 68 RRP samples (from 29 patients) were included. HPV type was determined. HPV viral load, physical status, and demographic and clinical characteristics were assessed. Immunohistochemistry (IHC) was performed for p16, Ki-67, L1, and E4. We used NanoSuit-CLEM (correlative light and electron microscopy) and transmission electron microscopy (TEM) to examine the samples. The total number of surgeries in HPV-positive and HPV-negative cases were 3.78 (n = 55/68, range: 1–16) and 1.30 (n = 13/68, range: 1–3), respectively (p = 0.02). IHC showed that L1 and E4 were correlated and expressed on the tumour surface. NanoSuit-CLEM and TEM revealed HPV particles in L1-positive nuclei. L1 IHC-positive cases had a shorter surgical interval (p < 0.01) and more frequent surgeries (p = 0.04). P16 IHC, viral load, and physical status were not associated with disease severity. This study visualised HPV particle production in RRP for the first time. Persistent HPV particle infection was associated with severity. We suggest L1 IHC for evaluating RRP severity in addition to the Derkay score.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dynamical Quantum Filtering via Enhanced Scattering of para-H2 on the Orientationally Anisotropic Potential of SrTiO3(001)

Koji Shimizu / Wilson Agerico Diño / Hiroshi Nakanishi / Hideaki Kasai / Kotaro Takeyasu / Katsuyuki Fukutani / Ayako Yajima

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 11

Abstract: Abstract Quantum dynamics calculation, performed on top of density functional theory (DFT)-based total energy calculations, show dynamical quantum filtering via enhanced scattering of para-H2 on SrTiO3(001). We attribute this to the strongly orientation- ... ...

Abstract	Abstract Quantum dynamics calculation, performed on top of density functional theory (DFT)-based total energy calculations, show dynamical quantum filtering via enhanced scattering of para-H2 on SrTiO3(001). We attribute this to the strongly orientation-dependent (electrostatic) interaction potential between the H2 (induced) quadrupole moment and the surface electric field gradient of ionic SrTiO3(001). These results suggest that ionic surfaces could function as a scattering/filtering media to realize rotationally state-resolved H2. This could find significant applications not only in H2 storage and transport, but also in realizing materials with pre-determined characteristic properties.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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