{"title":"Anatomical background of the sensory function in the urethra: involvement of endocrine paraneurons and afferent nerves in divergent urogenital functions. A review.","authors":"Toshihiko Iwanaga, Hiromi Takahashi-Iwanaga","doi":"10.2220/biomedres.43.187","DOIUrl":"https://doi.org/10.2220/biomedres.43.187","url":null,"abstract":"<p><p>The urethra is ontogenetically derived from the cloaca together with distal parts of the large intestine, and serotonin cells are predominant among dispersed endocrine/paracrine cells in the epithelia of both tissues. Analysis of urethral endocrine cells thus helps us to understand the functions of gut endocrine cells and their communication with the nervous system, due to the fact that the urethra is a simple tubular organ, where only urine without microflora rapidly passes through. A certain number of urethral endocrine cells display unique, complicated shapes with dendritic processes, reminiscent of neurons. Characteristically, urethral endocrine cells-often called paraneurons-have direct contact with sensory nerves within the epithelium, unlike gut endocrine cells lacking in direct contact with nerves. These traits encourage us to focus on the urethral paraneurons as ideal endocrine/paracrine cells. A topographical complex of urethral paraneurons and afferent nerve fibers is sensitive to the passage of urine or the distention of the urethral lumen. The urethra-bladder excitatory reflex facilitates micturition via the release of serotonin from the paraneurons, ultimately ensuring complete voiding of the bladder. This reflex may also influence sexual behaviors such as ejaculation or the female orgasm. Urethral brush cells as well as paraneurons are responsible for continuous monitoring of the mucosal surface, especially for pathogens entering via the external urethral orifice.</p>","PeriodicalId":9138,"journal":{"name":"Biomedical Research-tokyo","volume":"43 6","pages":"187-199"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10360797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RIPK1 is a key factor in black carbon-induced cell death.","authors":"Xianyan Xu, Zhaojun Xu, Shiyong Zeng, Yuhui Ouyang","doi":"10.2220/biomedres.43.23","DOIUrl":"https://doi.org/10.2220/biomedres.43.23","url":null,"abstract":"<p><p>Air pollution is associated with increased morbidity and mortality and with cell death at a cellular level. However, the exact mechanism of particulate matter-induced cell death remains to be elucidated. The aim of the present in vitro study using human alveolar epithelial cells (A549) was to determine the cell death pathway(s) induced by black carbon (BC) and ozone oxidized-black carbon (O-BC). BC and O-BC induced A549 cell death and the cytotoxic effect was dose-dependent. Cell death was significantly abrogated by inhibitor of receptor protein interacting kinase 1 (RIPK1) but only mildly inhibited by apoptosis inhibitor and RIPK3. BC- and O-BC-treated cells showed RIPK1 and RIPK3 protein overexpression and high phosphorylated levels of these proteins, as well as detectable levels of caspase-8 active form. BC- and O-BC-triggered cell death was also fully rescued in A549 cells that under-expressed RIPK1 with RIPK1 siRNA. Our results indicated that BC and O-BC could induce cell death through a multitude of pathways including apoptotic and necroptotic pathways and that RIPK1 is the upstream signal protein of these cell death pathways, with an important role in the regulation of BC-induced cell death.</p>","PeriodicalId":9138,"journal":{"name":"Biomedical Research-tokyo","volume":"43 1","pages":"23-30"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39626539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jing Qin, Wu-Shuang Huang, Hao-Ran DU, Chun-Qing Zhang, Peng Xie, Han Qin
{"title":"Ca<sup>2+</sup>-based neural activity recording for rapidly screening behavioral correlates of the claustrum in freely behaving mice.","authors":"Jing Qin, Wu-Shuang Huang, Hao-Ran DU, Chun-Qing Zhang, Peng Xie, Han Qin","doi":"10.2220/biomedres.43.81","DOIUrl":"https://doi.org/10.2220/biomedres.43.81","url":null,"abstract":"<p><p>The claustrum has been hypothesized to participate in high-order brain functions, but experimental studies to demonstrate these functions are currently lacking. Neural activity recording of the claustrum in freely-behaving animals allows for correlating claustral activities with specific behaviors. However, previously utilized methods for studying the claustrum make it difficult to monitor neural activity patterns of freely-behaving animals in real time. Here we applied fiber photometry to monitor Ca<sup>2+</sup> activity in the claustrum of freely-behaving mice. Using this method, we were able to achieve Ca<sup>2+</sup> activity recording in both anesthetized and freely-behaving mice. We found that the dynamics of Ca<sup>2+</sup> activity depended on anesthesia levels. As compared to the use of genetically encoded Ca<sup>2+</sup> indicators that requires a few weeks of virus-dependent expression, we used a synthetic fluorescent Ca<sup>2+</sup>-sensitive dye, Oregon green 488 BAPTA-1, that allows for rapidly screening neural activity of interest within a few hours that relates to certain behaviors. In this way, we found the correlation between Ca<sup>2+</sup> activity and specific behaviors, such as approaching an object. Our work offers an effective method for recording neural activity in the claustrum and thus for rapidly screening any behavioral relevance of the claustrum in freely-behaving mice.</p>","PeriodicalId":9138,"journal":{"name":"Biomedical Research-tokyo","volume":"43 3","pages":"81-89"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39998564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Meis1 plays roles in cortical development through regulation of cellular proliferative capacity in the embryonic cerebrum.","authors":"Eriko Isogai, Kazuhiro Okumura, Megumi Saito, Yurika Tokunaga, Yuichi Wakabayashi","doi":"10.2220/biomedres.43.91","DOIUrl":"https://doi.org/10.2220/biomedres.43.91","url":null,"abstract":"<p><p>Meis1 (myeloid ecotropic insertion site 1) is known to be related to embryonic development and cancer. In this study, to analyze the function of Meis1 in neural stem cells, we crossed Meis1<sup>fl/fl</sup> (Meis1 floxed) mice with Nestin-Cre mice. The results showed that Meis1-conditional knockout mice showed cerebral cortex malformation. The mice had a significantly thinner cortex than wildtype mice. At E14.5, BrdU incorporation and Pax6-positive radial glial cells were significantly decreased in the cerebral cortex of Meis1 knockout embryos as compared with wild-type embryos, whereas Tbr2-positive intermediate progenitors and NeuN-positive differentiated neurons were not. Cell death detected by immunostaining with cleaved caspase3 antibody showed no difference in the cortex between knockout and wild-type embryos. Furthermore, knockout of Meis1 in embryo by in utero electroporation showed that cellular migration was disturbed during cortical development. Therefore, Meis1 could play important roles during cortical development through the regulation of cell proliferation and migration in the embryonic cerebral cortex.</p>","PeriodicalId":9138,"journal":{"name":"Biomedical Research-tokyo","volume":"43 3","pages":"91-97"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39998565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Diet-related changes of basal lamina fenestrations in the villous epithelium of the rat small intestine: Statistical analysis on scanning electron microscopy.","authors":"Masatoshi Sato, Keisuke Morita, Rie Azumi, Yusuke Mizutani, Manabu Hayatsu, Tatsuo Ushiki, Shuji Terai","doi":"10.2220/biomedres.43.11","DOIUrl":"https://doi.org/10.2220/biomedres.43.11","url":null,"abstract":"<p><p>The epithelial basal lamina of the small intestine has numerous fenestrations for intraepithelial migration of leukocytes. We have reported dynamic changes of fenestrations in dietary conditions. To investigate this phenomenon, we performed statistical analyses using scanning electron microscopy images of the epithelial basal lamina of rat intestinal villi after removal of the villous epithelium by osmium maceration. We examined structural changes in the number and size of fenestrations in the rat jejunum and ileum under fasted and fed states for 24 h. Our findings revealed that, in the jejunum, the number of free cells migrating into the epithelium through fenestrations increased from 2 h after feeding, resulting in an increase in the fenestration size of intestinal villi; the number of free cells then tended to decrease at 6 h after feeding, and the fenestration size also gradually decreased. By contrast, the increase in the fenestration size by feeding was not statistically significant in the ileum. These findings indicate that the number of migrating cells increases in the upper part of the small intestine under dietary conditions, which may influence the absorption efficiency of nutrients including lipids, as well as the induction of nutrient-induced inflammation.</p>","PeriodicalId":9138,"journal":{"name":"Biomedical Research-tokyo","volume":"43 1","pages":"11-22"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39930231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structure and barrier functions of the perineurium and its relationship with associated sensory corpuscles: A review.","authors":"Toshihiko Iwanaga, Hiromi Takahashi-Iwanaga, Junko Nio-Kobayashi, Satomi Ebara","doi":"10.2220/biomedres.43.145","DOIUrl":"https://doi.org/10.2220/biomedres.43.145","url":null,"abstract":"<p><p>Peripheral nerves are provided with a blood-nerve barrier which prevents the invasion of harmful substances and pathogens, and also regulates metabolic and ionic homeostasis within nerve fascicles. The barrier functions are attributed to both the concentric layer of flattened cells in the perineurium and blood vessels running in the endoneurium. The perineurial cells develop continuous tight junctions as a diffusion barrier. In order to take up a predominant nutrient, glucose, the perineurium as well as endoneurial capillaries expresses GLUT1, a glucose transporter. An axon-Schwann cell complex within peripheral nerves utilizes glucose as a major energy source via the GLUT1, as does the brain. Under conditions of a reduced utilization of glucose, only the perineurial cells can transfer other nutrients, namely monocarboxylates such as ketone bodies and lactate via MCT1. Thus, MCT1 colocalizes with GLUT1 in the perineurium but not in endoneurial capillaries. To identify the cellular origins of the nerve sheath, marker proteins such as glial specific S100 protein, GLUT1, endoneurial CD34, and EMA (epithelial membrane antigen) are useful. Immunohistochemical findings for these markers are reviewed in this paper, focusing on the perineurium and endoneurium and their derivatives, Pacinian and Meissner corpuscles. Growing evidence throws light on the critical involvement of the nerve sheaths in the development, maintenance, and diseases of peripheral nerves.</p>","PeriodicalId":9138,"journal":{"name":"Biomedical Research-tokyo","volume":"43 5","pages":"145-159"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33512963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Selective estrogen receptor modulators, acting as agonists of estrogen receptor α in osteoblasts, reduce the TGF-β-induced synthesis of macrophage colony-stimulating factor via inhibition of JNK signaling pathway.","authors":"Tomoyuki Hioki, Rie Matsusima-Nishiwaki, Haruhiko Tokuda, Osamu Kozawa","doi":"10.2220/biomedres.43.211","DOIUrl":"https://doi.org/10.2220/biomedres.43.211","url":null,"abstract":"<p><p>Selective estrogen receptor modulator (SERM) binds to estrogen receptors (ERs) and acts as both an agonist or an antagonist, depending on the target tissue. Raloxifene and bazedoxifene as SERMs are currently used hormone replacement medicines for postmenopausal osteoporosis. Macrophage colony-stimulating factor (M-CSF) secreted from osteoblasts promotes osteoclastogenesis. We have previously demonstrated that transforming growth factor (TGF)-β induces the synthesis of M-CSF via SMAD2/3, p38 mitogen-activated protein kinase (MAPK), p44/p42 MAPK and c-Jun N-terminal kinase (JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether SERM affects the M-CSF synthesis by TGF-β in MC3T3-E1 cells. Raloxifene and bazedoxifene significantly suppressed the synthesis of M-CSF. PPT, an ERα agonist, but not ERB041, an ERβ agonist, inhibited the release of M-CSF. MPP, an ERα antagonist, reversed the suppression by raloxifene of the M-CSF release. Raloxifene attenuated the TGF-β-induced phosphorylation of JNK but not SMAD3, p42 MAPK and p38 MAPK. Bazedoxifene and PPT also inhibited the phosphorylation of JNK. Furthermore, MPP, an ERα antagonist, reversed the suppression by both raloxifene and bazedoxifene of the phosphorylation of JNK. Our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-β-induced synthesis of M-CSF through ERα-mediated inhibition of JNK pathway in osteoblasts.</p>","PeriodicalId":9138,"journal":{"name":"Biomedical Research-tokyo","volume":"43 6","pages":"211-221"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10427662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Secondary bile acid lithocholic acid attenuates neurally evoked ion transport in the rat distal colon.","authors":"Kohei Takahashi, Yuko Kuwahara, Ikuo Kato, Shinji Asano, Takaharu Kozakai, Yoshinori Marunaka, Atsukazu Kuwahara","doi":"10.2220/biomedres.43.223","DOIUrl":"https://doi.org/10.2220/biomedres.43.223","url":null,"abstract":"<p><p>The inhibitory action of the secondary bile acid lithocholic acid (LCA) on neurally evoked Cl<sup>-</sup>/HCO<sub>3</sub><sup>-</sup> secretion was investigated using the Ussing-chambered mucosal-submucosal preparation from the rat distal colon. Electrical field stimulation (EFS) evoked cholinergic and noncholinergic secretory responses in the rat distal colon. The responses were almost completely blocked by TTX (10<sup>-6</sup> M) but not atropine (10<sup>-5</sup> M) or hexamethonium (10<sup>-4</sup> M). The selective antagonist for VIP receptor 1 (VPAC1) greatly reduced the EFS-evoked response. Thus, the rat distal colon may be predominantly innervated by noncholinergic VIP secretomotor neurons. Basolateral addition of 6 × 10<sup>-5</sup> M LCA inhibited the EFS-evoked response. The inhibitory action of LCA was partly rescued by the Y2R antagonist BIIE0246. The bile acid receptor TGR5 agonist INT-777 mimicked the LCA-induced inhibitory action. Immunohistochemical staining showed the colocalization of TGR5 and PYY on L cells. TGR5 immunoreactivity was also found in VIP-immunoreactive submucosal neurons which also expressed the PYY receptor, Y2R. These results suggest that LCA inhibits neurally evoked Cl<sup>-</sup>/HCO<sub>3</sub><sup>-</sup> secretion through the activation of TGR5 on L cells and cholinergic- and VIP-secretomotor neurons in the submucosal plexus. Furthermore, the inhibitory mechanism may involve TGR5-stimulated PYY release from L cells and Y2R activation in VIP-secretomotor neurons.</p>","PeriodicalId":9138,"journal":{"name":"Biomedical Research-tokyo","volume":"43 6","pages":"223-239"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10355112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CD44 as a pathological marker for the early detection of calcineurin inhibitor-induced nephrotoxicity post kidney transplantation.","authors":"Asako Hayashi, Takayuki Okamoto, Junko Nio-Kobayashi, Naoya Iwahara, Ryota Suzuki, Yasuhiro Ueda, Toshiyuki Takahashi, Yasuyuki Sato, Toshihiko Iwanaga, Kiyohiko Hotta","doi":"10.2220/biomedres.43.181","DOIUrl":"https://doi.org/10.2220/biomedres.43.181","url":null,"abstract":"<p><p>Long-term calcineurin inhibitor (CNI) administration causes irreversible nephrotoxicity. Therefore, early CNI-induced nephrotoxicity detection is necessary for patients who will need long-term CNI administration. There is no pathological indicator for early CNI-induced nephrotoxicity. Here, serial protocol kidney biopsy specimens from five kidney-transplant patients with severe CNI-induced nephrotoxicity were examined. We observed that the increase in CD44 expression in glomerular parietal epithelial cells (PECs) preceded the chronic pathological changes of CNI-induced nephrotoxicity such as tubular atrophy/interstitial fibrosis, arterial hyaline thickening, and focal segmental glomerulosclerosis (FSGS). This result suggests that CD44-positive PECs have pivotal roles in FSGS development in human CNI-induced nephrotoxicity as well as rodent models. CD44 could be useful as a pathological marker for early CNI-induced nephrotoxicity detection post kidney transplantation.</p>","PeriodicalId":9138,"journal":{"name":"Biomedical Research-tokyo","volume":"43 5","pages":"181-186"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33512931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Disposal of intestinal apoptotic epithelial cells and their fate via divergent routes.","authors":"Toshihiko Iwanaga, Hiromi Takahashi-Iwanaga","doi":"10.2220/biomedres.43.59","DOIUrl":"https://doi.org/10.2220/biomedres.43.59","url":null,"abstract":"<p><p>Gut epithelial cells are characterized by rapid, constant cell renewal. The disposal of aging epithelial cells around the villus tips of the small intestine occurs so regularly that it has been regarded as a consequence of well-controlled cell death, designated as apoptosis. However, the notion of live cell extrusion in the intestine has been intensively built among researchers, and the disposal processes of effete epithelial cells display species and regional differences. Chemical mediators and mechanical forces rising from surrounding cells contribute to the regulated cell replacement. Cytotoxic intraepithelial lymphocytes and lamina propria macrophages play a leading role in the selection of disposal cells and their extrusion to maintain fully the epithelial homeostasis in tandem with the dynamic reconstruction of junctional devices. Lymphocyte-mediated cell killing is predominant in the mouse and rat, while the disposal of epithelial cells in the guinea pig, monkey, and human is characterized by active phagocytosis by subepithelially gathering macrophages. The fenestrated basement membrane formed by immune cells supports their involvement and explains species differences in the disposal of epithelial cells. Via these fenestrations, macrophages and dendritic cells can engulf apoptotic epithelial cells and debris and convey substantial information to regional lymph nodes. In this review, we attempt to focus on morphological aspects concerning the apoptosis and disposal process of effete epithelial cells; in vitro or ex vivo analyses using cultured monolayer has become predominant in recent studies concerning the exfoliation of apoptotic enterocytes. Furthermore, we give attention to their species differences, which is controversial but crucial to our understanding.</p>","PeriodicalId":9138,"journal":{"name":"Biomedical Research-tokyo","volume":"43 3","pages":"59-72"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39997753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}