Language：English   Publishing type：Research paper (scientific journal)  

Lower urinary tract symptoms (LUTS) significantly affect patient quality of life. Treatment options for bladder outlet obstruction (BOO) due to benign prostatic hyperplasia (BPH) (a common cause of LUTS) are insufficient to relieve discomfort. As the incidence of BPH is increasing, new pharmacological targets for LUTS treatment are required. Corticotropin-releasing hormone (CRH) is a neuropeptide that controls normal micturition in rodents. Herein, we investigated the role of spinal CRH in regulating micturition in sham and BOO rats, and evaluated CRH as a therapeutic target for bladder dysfunction in BOO model Sprague-Dawley rats. Histological analysis, cystometry with intrathecal administration of CRH agonists/antagonists, western blotting, and real-time PCR assessed the role of CRH and its receptors (CRHR1 and CRHR2) in micturition in sham and BOO rats. CRH administration shortened the voiding interval, while pretreatment with antagonists against CRHR2 (but not CRHR1) suppressed CRH-induced frequent voiding. Western blotting confirmed CRHR1 expression in the dorsal root ganglia (DRG) and bladder, but not the spinal cord, of rats. Real-time PCR showed higher CRHR2 mRNA expression in the spinal cord and DRG than in the bladder in both groups. Overall, spinal CRH facilitates the micturition reflex via CRHR2, and is a promising therapeutic target for LUTS.

DOI： 10.1038/s41598-025-87990-w

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In goldfish, spinal cord injury triggers the formation of a fibrous scar at the injury site. Regenerating axons are able to penetrate the scar tissue, resulting in the recovery of motor function. Previous findings suggested that regenerating axons enter the scar through tubular structures surrounded by glial elements with laminin-positive basement membranes and that glial processes expressing glial fibrillary acidic protein (GFAP) are associated with axonal regeneration. How glia contribute to promoting axonal regeneration, however, is unknown. Here, we revealed that glial processes expressing vimentin or brain lipid-binding protein (BLBP) also enter the fibrous scar after spinal cord injury in goldfish. Vimentin-positive glial processes were more numerous than GFAP- or BLBP-positive glial processes in the scar tissue. Regenerating axons in the scar tissue were more closely associated with vimentin-positive glial processes than GFAP-positive glial processes. Vimentin-positive glial processes co-expressed matrix metalloproteinase (MMP)-14. Our findings suggest that vimentin-positive glial processes closely associate with regenerating axons through tubular structures entering the scar after spinal cord injury in goldfish. In intact spinal cord, ependymo-radial glial cell bodies express BLBP and their radial processes express vimentin, suggesting that vimentin-positive glial processes derive from migrating ependymo-radial glial cells. MMP-14 expressed in vimentin-positive glial cells and their processes might provide a beneficial environment for axonal regeneration.

DOI： 10.1007/s00441-024-03907-5

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Abstract

In addition to an oral jaw, cichlids have a pharyngeal jaw, which is used for crushing and processing captured prey. The teeth and morphology of the pharyngeal jaw bones adapt to changes in prey in response to changes in the growing environment. This study aimed to explore the possible involvement of the peripheral nervous system in remodeling the cichlid pharyngeal jaw by examining the innervation of the inferior pharyngeal jaw in the Nile tilapia, Oreochromis niloticus. Vagal innervation was identified in the Nile tilapia inferior pharyngeal jaw. Double staining with tartrate‐resistant acid phosphatase and immunostaining with the neuronal markers, protein gene product 9.5, and acetylated tubulin, revealed that osteoclasts, which play an important role in remodeling, were distributed in the vicinity of the nerves and were in apposition with the nerve terminals. This contact between peripheral nerves and osteoclasts suggests that the peripheral nervous system may play a role in remodeling the inferior pharyngeal jaw in cichlids.

DOI： 10.1002/ar.25381

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The renin-angiotensin system in the brain plays a pivotal role in modulating sympathetic nerve activity and contributes to the pathogenesis of hypertension. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R while suppressing pathological overactivation of AT1R signaling. However, the pathophysiological function of ATRAP in the brain remains unknown. Therefore, this study aims to investigate whether ATRAP in the paraventricular nucleus (PVN) is involved in neurogenic hypertension pathogenesis in Ang II-infused rats. The ATRAP/AT1R ratio, which serves as an indicator of tissue AT1R hyperactivity, tended to decrease within the PVN in the Ang II group than in the vehicle group. This suggests an Ang II-induced hyperactivation of the AT1R signaling pathway in the PVN. Lentiviral vectors were generated to stimulate ATRAP expression. At 6 weeks of age, rats were microinjected with LV-Venus (Venus-expressing lentivirus) or LV-ATRAP (Venus-ATRAP-expressing lentivirus). The rats were then randomly divided into four groups: (1) Vehicle/LV-Venus, (2) Vehicle/LV-ATRAP, (3) Ang II/LV-Venus, and (4) Ang II/LV-ATRAP. Two weeks after microinjection, vehicle or Ang II was administered systemically for 2 weeks. In the Ang II/LV-ATRAP group, systolic blood pressure at 1 and 2 weeks following administration was significantly lower than that in the Ang II/LV-Venus group. Furthermore, urinary adrenaline levels tended to decrease in the Ang II/LV-ATRAP group than in the Ang II/LV-Venus group. These findings suggest that enhanced ATRAP expression in the PVN suppresses Ang II-induced hypertension, potentially by suppressing hyperactivation of the tissue AT1R signaling pathway and, subsequently, sympathetic nerve activity.

DOI： 10.1038/s41440-023-01480-y

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Corneal astigmatism is reportedly associated with polymorphisms of the platelet-derived growth factor receptor alpha (PDGFRA) gene region in Asian populations of Chinese, Malay, and Indian ancestry and populations of European ancestry. In this study, we investigated whether these PDGFRA polymorphisms are associated with corneal astigmatism in a Japanese population. We recruited 1,535 cases with corneal astigmatism (mean corneal cylinder power across both eyes: ≤  - 0.75 diopters [D]) and 842 controls (> - 0.75 D) to genotype 13 single-nucleotide polymorphisms (SNPs) in the PDGFRA gene region. We also performed imputation analysis in the region, with 179 imputed SNPs included in the statistical analyses. The PDGFRA SNPs were not significantly associated with the cases with corneal astigmatism ≤  - 0.75 D. However, the odds ratios (ORs) of the minor alleles of SNPs in the upstream region of PDGFRA, including rs7673984, rs4864857, and rs11133315, tended to increase according to the degree of corneal astigmatism, and these SNPs were significantly associated with the cases with corneal astigmatism ≤  - 1.25 D or ≤  - 1.50 D (Pc < 0.05, OR = 1.34-1.39). These results suggest that PDGFRA SNPs play a potential role in the development of greater corneal astigmatism.

DOI： 10.1038/s41598-023-43333-1

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Spinal cord injury in teleosts leads to a fibrous scar, but axons sometimes spontaneously regenerate beyond the scar. In goldfish, regenerating axons enter the scar through tubular structures and enlargement of the tubular diameter is proportional to the increase in the number of regenerating axons. During the regeneration process, mast cells containing 5-hydroxytryptamine (5HT) are recruited to the injury site, and 5HT neurons are newly generated. Here, we investigated the distribution of 5HT receptors during this process to determine their role in remodeling the fibrous scar and tubular structures. At 2 weeks after spinal cord transection (SCT) in goldfish, expression of the 5HT2A and 5HT2C receptor subtypes was observed in the ependymo-radial glial cells lining the central canal of the spinal cord. 5HT2A was expressed at the luminal surface, suggesting that it is receptive to 5HT in the cerebrospinal fluid. 5HT2C, on the other hand, was expressed around the nuclei and in the radial processes protruding from the basal surface, suggesting that it is receptive to 5HT released from nearby nerve endings. 5HT2C was also expressed in the fibrous scar where mast cells containing 5HT were abundant. 5HT1B expression was coincident with the basement membrane bordering the fibrous scar and the surrounding nervous tissue, and with the basement membrane of the tubular structure through which axons pass during regeneration. Our findings suggest that multiple 5HT receptors are involved in remodeling the injured site during the regenerative process following SCT. Ependymo-radial glial cells expressing 5HT2A and 5HT2C are involved in neurogenesis and gliogenesis, which might contribute to remodeling the fibrous scar in coordination with 5HT-containing mast cells. Coincident expression of 5HT1B with the basement membrane might be involved in remodeling the tubular structures, thereby promoting axonal regeneration.

DOI： 10.1016/j.jchemneu.2023.102281

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Considering the prevalence of obesity and global aging, the consumption of a high-protein diet (HPD) may be advantageous. However, an HPD aggravates kidney dysfunction in patients with chronic kidney disease (CKD). Moreover, the effects of an HPD on kidney function in healthy individuals are controversial. In this study, we employed a remnant kidney mouse model as a CKD model and aimed to evaluate the effects of an HPD on kidney injury under conditions of non-CKD and CKD. Mice were divided into four groups: a sham surgery (sham) + normal diet (ND) group, a sham + HPD group, a 5/6 nephrectomy (Nx) + ND group and a 5/6 Nx + HPD group. Blood pressure, kidney function and kidney tissue injury were compared after 12 weeks of diet loading among the four groups. The 5/6 Nx groups displayed blood pressure elevation, kidney function decline, glomerular injury and tubular injury compared with the sham groups. Furthermore, an HPD exacerbated glomerular injury only in the 5/6 Nx group; however, an HPD did not cause kidney injury in the sham group. Clinical application of these results suggests that patients with CKD should follow a protein-restricted diet to prevent the exacerbation of kidney injury, while healthy individuals can maintain an HPD without worrying about the adverse effects.

DOI： 10.3390/ijms24097778

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1227/neuopn.0000000000000019

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Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in βUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of β-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of β-cell function.

DOI： 10.1016/j.isci.2022.104603

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Chondroitinase ABC (ChABC) is an enzyme that degrades glycosaminoglycan side-chains of chondroitin sulfate (CS-GAG) from the chondroitin sulfate proteoglycan (CSPG) core protein. Previous studies demonstrated that the administration of ChABC after spinal cord injury promotes nerve regeneration by removing CS-GAGs from the lesion site and promotes the plasticity of spinal neurons by removing CS-GAGs from the perineuronal nets (PNNs). These effects of ChABC might enhance the regeneration and sprouting of descending axons, leading to the recovery of motor function. Anatomical evidence, indicating that the regenerated axons innervate spinal motoneurons caudal to the lesion site, however, has been lacking. In the present study, we investigated whether descending axons pass through the lesion site and innervate the lumbar motoneurons after ChABC administration in rats with complete spinal cord transection (CST) at the thoracic level. At 3 weeks after CST, 5-hydroxytryptamine (5-HT) fibers were observed to enter the lesion in ChABC-treated rats, but not saline-treated rats. In addition, 92% of motoneurons in the ventral horn of the fifth lumbar segment (L5) in saline-treated rats, and 38% of those in ChABC-treated rats were surrounded by chondroitin sulfate-A (CS-A) positive structures. At 8 weeks after CST, many 5-HT fibers were observed in the ventral horn of the L5, where they terminated in the motoneurons in ChABC-treated rats, but not in saline-treated rats. In total, 54% of motoneurons in the L5 ventral horn in saline-treated rats and 39% of those in ChABC-treated rats were surrounded by CS-A-positive structures. ChABC-treated rats had a Basso, Beattie, and Bresnahan (BBB) motor score of 3.8 at 2 weeks, 7.1 at 3 weeks, and 10.3 at 8 weeks after CST. These observations suggest that ChABC administration to the lesion site immediately after CST may promote the regeneration of descending 5-HT axons through the lesion site and their termination on motoneurons at the level of caudal to the lesion site. ChABC administration might facilitate reinnervation by degrading CS-GAGs around motoneurons. Motor function of the lower limbs was significantly improved in ChABC-treated rats even before the 5-HT axons terminated on the motoneurons, suggesting that other mechanisms may also contribute to the motor function recovery.

DOI： 10.3389/fnint.2022.881632

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In the acute phase of spinal cord injury, the initial injury triggers secondary damage due to neuroinflammation, leading to the formation of cavities and glial scars that impair nerve regeneration. Following injuries to the central nervous system, early mobilization promotes the recovery of physical function. Therefore, in the present study, we investigated the effects of early mobilization on motor function recovery and neuroinflammation in rats. Early mobilization of rats with complete spinal cord transection resulted in good recovery of hindlimb motor function after 3 weeks. At 1 week after spinal cord injury, the early-mobilized rats expressed fewer inflammatory M1 microglia/macrophages and more anti-inflammatory M2 microglia. In addition, significantly more matrix metalloproteinase 2 (MMP2)-positive cells were observed at the lesion site 1 week after injury in the early-mobilized rats. Multiple labeling studies suggested that many MMP2-positive cells were M2 microglia. MMP9-positive cells that highly co-expressed GFAP were also observed more frequently in the early-mobilized rats. The density of growth-associated protein-positive structures in the lesion center was significantly higher in the early-mobilized rats at 3 weeks after spinal cord injury. The present results suggest that early mobilization after spinal cord injury reduced the production of M1 microglia/macrophages while increasing the production of M2 microglia at the lesion site. Early mobilization might also activate the expression of MMP2 in M2 microglia and MMP9 in astrocytes. These cellular dynamics might suppress neuroinflammation at the lesion site, thereby inhibiting the progression of tissue destruction and promoting nerve regeneration to recover motor function.

DOI： 10.1016/j.ibneur.2022.04.002

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The thalamic reticular nucleus (TRN) projects inhibitory signals to the thalamus, thereby controlling thalamocortical connections. Few studies have examined the development of TRN projections to the anterior thalamic nuclei with regard to axon course and the axon terminal distributions. In the present study, we used parvalbumin (PV) immunostaining to investigate inhibitory projections from the TRN to the thalamus in postnatal (P) 2- to 5-week-old rats (P14-35). The distribution of PV-positive (+) nerve fibers and nerve terminals markedly differed among the anterior thalamic nuclei at P14. Small, beaded nerve terminals were more distributed throughout the anterodorsal nucleus (AD) than in the anteroventral nucleus (AV) and anteromedial nucleus (AM). PV+ fibers traveling from the TRN to the AD were observed in the AV and AM. Nodular nerve terminals, spindle or en passant terminals, were identified on the axons passing through the AV and AM. At P21, axon bundles traveling without nodular terminals were observed, and nerve terminals were distributed throughout the AV and AM similar to the AD. At P28 and P35, the nerve terminals were evenly distributed throughout each nucleus. In addition, DiI tracer injections into the retrosplenial cortex revealed retrogradely-labeled projection neurons in the 3 nuclei at P14. At P14, the AD received abundant projections from the TRN and then projected to the retrosplenial cortex. The AV and AM seem to receive projections with distinct nodular nerve terminals from the TRN and project to the retrosplenial cortex. The projections from TRN to the AV and AM with nodular nerve terminals at P14 are probably developmental-period specific. In comparison, the TRN projections to the AD at P14 might be related to the development of spatial navigation as part of the head orientation system.

DOI： 10.4081/ejh.2022.3370

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Hind limb locomotor activity spontaneously recovers after complete spinal transection (CST) in neonatal rats, but the mechanisms underlying the recovery are poorly understood. The perineuronal net (PNN) surrounding the neuronal cell bodies comprises an extracellular matrix that regulates neuronal plasticity during development. Here, we examined the expression of chondroitin sulfate (CS), a major component of the PNN, on motoneurons after CST in neonatal rats, and compared it with that in juvenile rats, in which hindlimb locomotor activity does not recover spontaneously. The spinal cord was transected at the mid-thoracic level in neonatal (postnatal day 5 [P5] and P10) and juvenile (P15 and P20) rats. Two weeks after CST, the percentage of motoneurons surrounded by chondroitin sulfate C (CS-C) - positive structures was significantly lower in rats with CST at P10 than in intact rats, and tended to be higher in rats with CST at P15 than in intact rats. The percentage of motoneurons with CS-A - positive structures was significantly lower in rats with CST at P15 than in intact rats. These findings suggest that CS-A and CS-C are differentially expressed in the PNNs in rats with CST. The decrease in CS-C - positive PNNs might facilitate the formation of new synaptic contacts to motoneurons, resulting in the recovery of the hindlimb locomotor activity in rats with CST during the neonatal period.

DOI： 10.1016/j.neulet.2021.136324

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Spinal cord injury in fish produces fibrous scar, but spontaneous axonal regeneration beyond the scar sometimes occurs. A previous study revealed that regenerating axons enter the scar through tubular structures with laminin, and that an increased number of axons within the tube is coincident with enlargement of the tube diameter and reduction of the fibrous scar area. The present study investigated the expression of matrix metalloproteinases (MMPs) that might play a role in the degradation of the extracellular matrix in fibrous scar tissue and in the remodeling of tubular structures. Spinal hemisection produced fibrous scar tissue in the lesion center, surrounded by nervous tissue. Two weeks after spinal lesioning, MMP-9 was expressed in some regenerating axons in the fibrous scar tissue. MMP-14 was expressed in the regenerating axons, as well as in glial processes in the fibrous scar tissue. MMP-2 was suggested to be expressed in mast cells in the fibrous scar. The mast cells were in contact with fibroblasts, and in close proximity to the basement membrane of tubular structures surrounding the regenerating axons. The present findings suggest that several MMPs are involved in axon regenerating processes following spinal cord injury in goldfish. MMP-9 and MMP-14 expressed in the regenerating axons might degrade extracellular matrix and support axonal growth deep into the fibrous scar tissue. MMP-14 expressed in glial cells and MMP-2 expressed in mast cells might also provide a beneficial environment for axonal regeneration, leading to successful motor recovery.

DOI： 10.1016/j.jchemneu.2021.102041

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The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.

DOI： 10.3390/ijms222212432

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Nicotine exerts its reinforcing actions by activating nicotinic acetylcholine receptors (nAChRs), but the detailed mechanisms remain unclear. Nicotine releases 3, 4-dihydroxyphenylalanine (DOPA), a neurotransmitter candidate in the central nervous system. Here, we investigated the distribution of GPR143, a receptor of DOPA, and nAChR subunits in the nigrostriatal and mesolimbic regions. We found GPR143 mRNA-positive cells in the striatum and nucleus accumbens. Some of them were surrounded by tyrosine hydroxylase (TH)-immunoreactive fibers. There were some GPR143 mRNA-positive cells coexpressing TH, and nAChR subunit α4 or α7 in the substantia nigra and ventral tegmental area. These findings suggest that DOPA-GPR143 signaling may be involved in the nicotine action in the nigrostriatal and mesolimbic dopaminergic systems.

DOI： 10.1016/j.neures.2020.08.003

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BACKGROUND: The occipital transtentorial approach (OTA) is a very useful but challenging approach to expose the pineal region because the deep-seated arachnoid membranes usually fold and extend over the great vein of Galen (GVG), leading to dense and poor visibility. In addition, the practical aspects of arachnoid anatomy are not well understood. We aimed to develop a safe surgical procedure for the OTA according to the practical aspects of arachnoid anatomy. METHODS: The procedure is shown through an illustrative video of surgery and cadaver. Five cadavers were analyzed for their arachnoid structures and the surgical procedures via the OTA, in strict compliance with legal and ethical requirements. RESULTS: All cadavers showed a 2-layered arachnoid structure-one belonging to the occipital lobe, and the other to the cerebellum. According to our cadaveric analysis, the arachnoid attachment of the tentorial apex can be peeled bluntly, with an average distance of 10.2 mm. For our clinical presentation, a pineal tumor with hydrocephalus was detected in a 14-year-old boy. While using the OTA and expanding the deep surgical field, we detached the membrane from the tentorial apex and bluntly peeled it to reveal the deep veins. Finally, gross total removal of the tumor was achieved. CONCLUSIONS: A 2-layered arachnoid structure interposes the GVG from above and below the tentorium. The arachnoid membrane below the tentorium can be peeled off bluntly from the GVG to the attachment bundle limited by the penetrating veins. This detachment technique is useful for safe enlargement of the surgical field for the OTA.

DOI： 10.1016/j.wneu.2021.04.041

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Perineuronal nets are extracellular matrix structures that surround neuronal cell bodies and their proximal dendrites in the central nervous system. Chondroitin sulfate proteoglycans, which contain chondroitin sulfates (CSs) are major components of perineuronal nets. CSs are considered to have inhibitory roles in neural plasticity, although the effects differ according to their sulfation pattern. In the present study, we investigated the expression of the CS subtypes CS-A and CS-C surrounding spinal motoneurons in different postnatal periods to explore the potential influence of altered CS sulfation patterns on spinal development. CS-A-positive structures were observed around motoneurons in the cervical, thoracic, and lumbar segments as early as postnatal day (P) 5. Most motoneurons were covered with CS-A-positive structures during the first 2 postnatal weeks. The percentage of motoneurons covered with CS-A-positive structures decreased after P20, becoming lower than 70% in the cervical, and lumber segments after P35. CS-C-positive structures were occasionally observed around motoneurons during the first 2 postnatal weeks. The percentage of motoneurons covered with CS-C-positive structures increased after P20, becoming significantly higher after P25 than before P20. The expression pattern of Wisteria Floribunda agglutinin-positive structures around motoneurons was similar to that of the CS-C-positive structures. The present findings revealed that CS-A and CS-C are differentially expressed in the extracellular matrix surrounding motoneurons. The altered sulfation pattern with increased CS-C expression is associated with the maturation of perineuronal nets and might lead to changes in the motoneuron plasticity.

DOI： 10.1016/j.brainres.2020.147252

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O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.

DOI： 10.1016/j.celrep.2020.108579

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Exosomes contain many proteins associated with neurodegenerative diseases. To identify new candidate biomarkers and proteins associated with amyotrophic lateral sclerosis (ALS), we performed liquid chromatography-tandem mass spectrometry proteomic analysis of exosome-enriched fractions isolated from cerebrospinal fluid (CSF) of sporadic ALS patients using gel filtration chromatography. Proteomic data revealed that three proteins were increased and 11 proteins were decreased in ALS patients. The protein with the greatest increase in exosome-enriched fractions of CSF derived from ALS was novel INHAT repressor (NIR), which is closely associated with nucleolar function. By immunohistochemical analysis, we found that NIR was reduced in the nucleus of motor neurons in ALS patients. Our results demonstrate the potential utility of our methodology for proteomic analysis of CSF exosomes and suggest that nucleolar stress might play a role in sporadic ALS pathogenesis through the dysfunction of NIR.

DOI： 10.1016/j.neures.2019.10.010

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Thiel's embalming method provides natural coloration, flexibility, and tissue plasticity, and is used widely to prepare specimens for cadaver surgical training. However, this method causes brain softening, thereby restricting the cadaver surgical training of intra-cranial procedures. In this study, three cadavers were embalmed using formalin fixation, Thiel's embalming method, and Thiel's embalming method with additional intra-cerebral ventricular formalin injection, respectively. We also established rat models of the three embalming methods to develop and determine the best method for retaining adequate brain elasticity. The intra-ventricular formalin injection in the cadaver was performed through the Kocher's point, as in the classical external ventricular drain procedure. Both, the cadaver brains and rat models yielded consistent shear wave measurements and brain surface stiffness data. Notably, the Thiel's embalming method with additional intra-cerebral ventricular formalin injection yielded suitable elasticity for brain cadaver surgical training in terms of brain mobilization and surgical field deployment, and also discharged formaldehyde in undetectable quantities. To our knowledge, this is the first report in which a fixed quality, namely, brain elasticity for the performance of head and brain cadaver surgical training, has been evaluated in a cadaver subjected to the Thiel's embalming method with immersion fixation in the cerebrospinal fluid space. We conclude that the Thiel's embalming method with additional intra-cerebral ventricular formalin injection can maintain the brain elasticity, and may therefore improve the quality of head and brain cadaver surgical training safely and easily.

DOI： 10.1007/s12565-020-00545-z

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DOI： 10.1016/j.bbrc.2018.09.151

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DOI： 10.1016/j.ibror.2017.11.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Mary Ann Liebert Inc.  

DOI： 10.1089/ther.2017.0013

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media S.A.  

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DOI： 10.3389/fncel.2018.00063

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DOI： 10.1016/j.brainres.2017.08.004

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DOI： 10.1038/s41598-017-12449-6

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DOI： 10.1159/000455962

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DOI： 10.1016/j.neuroscience.2015.07.046

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DOI： 10.1186/s12990-015-0039-9

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DOI： 10.1111/azo.12068

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DOI： 10.1016/j.neuroscience.2014.09.066

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DOI： 10.1016/j.bbrc.2014.01.082

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DOI： 10.1016/j.neures.2013.08.011

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Authorship：Last author   Language：Japanese   Publishing type：Research paper (scientific journal)  

In order to develop a portable leukocytapheresis system, an animal pilot study was performed using a blood-circulating tube of 3 mm in ID, and 40 cm in length having a leukocyte wall-trap made up of 2 kinds of fabric, 7 cm in length each, on the luminal wall. One fabric tube was made of ultra-fine (3.3 μOD) polyester fibers (UFPFs), and the other was made of regular-sized (16 μOD) polyester fibers (RPFs). This was based on the rolling phenomenon of leukocytes in a small caliber blood vessel wall, the laminar flow phenomenon, and the thygmotaxis phenomenon. Blood circulation from the left jugular vein to the left femoral vein was performed for two hours in a dog treated with heparin without using any pump. The amount of blood flow in the tube was approximately 160 ml/min. Sections of each fabric were examined light-microscopically. Leukocytes were trapped in the interstices of UFPFs 5 times more than in RPFs. Leukocytes were effectively trapped under a condition of low blood-flow resistance. These results indicated that leukocyte wall-trapping with UFPFs is effective. A portable leukocytapheresis system will be devised using wall-trapping in the near future.

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Other Link： http://id.nii.ac.jp/1141/00152217/

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.18892/jsnas.13.3_219

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.12072

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DOI： 10.3171/2013.4.SPINE12683

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DOI： 10.1016/j.bbrc.2013.01.103

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/978-1-62703-444-9_31

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Language：Japanese   Publisher：(一社)日本脊椎脊髄病学会  

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Authorship：Last author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Physical Therapy Association (JPTA)  

Introduction: The purpose of this study was to examine the compensatory mechanism in rats, underwent left decortication at postnatal day 7 by using retrograde tracing method. Methods: Retrograde tracers, FITC-conjugated CTB and FastBlue were injected into the right and the left sides of upper cervical segments of spinal cord, respectively, at postoperative weeks 2, 3, 4, and 5. The number of retrogradely labeled descending projective neurons was compared to the number of the same neurons in normally developed rats. Results: Significantly more ipsilateral corticospinal neurons were labeled with FITC-CTB in the experimental rats compared to normal rats at all cases. There were also some FITC-CTB and FB double-labeled corticospinal neurons in both experimental and normal rats. In decorticated rats the number of doubly labeled neurons increased sequentially, and was significantly greater than in normal rats at postoperative weeks 4 and 5. However, only few percent of all neurons were double labeled in the treated animals. Significantly more neurons were also labeled with FITC-CTB in the medullary ventral reticulospinal area and in the medullary raphe-spinal area in the experimental rats compared to control animals at postoperative weeks 4 and 5. Conclusion: The present results suggest that main compensatory response after unilateral neonatal decortication was formed by unlesioned ipsilateral corticospinal neurons, which were not selective in development. Furthermore, the collaterals of the corticospinal tracts originate from the cerebral cortex on the unlesioned side and descending spinal projections from brainstem are also related to compensatory response.

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ijdevneu.2011.05.007

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(一社)日本脊椎脊髄病学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neures.2010.09.006

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

To examine the compensatory mechanisms in rats that underwent left decortication at postnatal day 7 (P7), we injected the retrograde tracers fluorescein isothiocyanate-cholera toxin B subunit (FITC-CTB) and Fast Blue (FB) into the right and left upper cervical spinal cord, respectively, at postoperative weeks 2, 3, 4, and 5 and counted the number of retrogradely labeled corticospinal neurons in the right cerebral cortex compared with that in normally developed rats. Significantly more ipsilaterally projecting neurons were labeled with FITC-CTB in the decorticated rats compared with normal rats at all time points examined. The number of labeled neurons was similar to that at P7 in normal rats. There were also some FITC-CTB and FB double-labeled neurons in both decorticated and normal rats. The number of double-labeled neurons in the decorticated rats increased each week and was significantly greater than that in normal rats at postoperative weeks 4 and 5. The present results suggest that the elimination of ipsilaterally projecting axons observed in normal rats was prevented in the decorticated rats, so that the cerebral cortex neurons on the unlesioned side projected corticospinal tracts to the ipsilateral spinal cord. Furthermore, the collaterals of the corticospinal tracts originating from the cerebral cortex on the unlesioned side also project to the ipsilateral spinal cord. These compensatory mechanisms might underlie the acquisition of motor function in these animals.

DOI： 10.1159/000335526

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.brainres.2009.02.020

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DOI： 10.1002/cne.21956

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DOI： 10.1159/000219486

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DOI： 10.3171/JNS/2008/109/7/0083

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DOI： 10.1111/j.1348-0421.2008.00044.x

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbi.2007.08.013

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neuroscience.2007.10.059

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/13693780802039919

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.brainres.2007.04.020

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DOI： 10.1080/10739680601131184

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000095199

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neulet.2006.08.067

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00418-006-0167-4

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DOI： 10.1152/ajpheart.00100.2004

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DOI： 10.1007/s00441-005-0013-3

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DOI： 10.1016/j.neulet.2005.02.047

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DOI： 10.1002/cne.20081

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/S0165-3806(03)00165-2

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/S0026-2862(03)00003-7

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DOI： 10.1002/cne.10514

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DOI： 10.1034/j.1399-0039.2002.600506.x

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DOI： 10.1002/cne.10276

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DOI： 10.1016/S0361-9230(02)00814-6

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DOI： 10.1016/S1566-0702(02)00061-9

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/cne.10238

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DOI： 10.1002/cne.10082

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DOI： 10.1016/S0304-3940(01)02386-2

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ar.1071

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/1096-9861(20001204)428:1<174::AID-CNE12>3.0.CO;2-U

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/1097-0185(20001101)260:3<299::AID-AR67>3.0.CO;2-V

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/S1566-0702(00)00195-8

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/S0361-9230(00)00295-1

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DOI： 10.1016/S0165-1838(00)00073-4

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Serotonin-immunoreactive axonal components were observed in the central autonomic nucleus (CAN), a cell column of sympathetic preganglionic neurons in the rostral spinal card of the filefish Stephanolepis cirrhifer. Serotonin-positive axonal varicosities were seen around neuronal perikarya through the whole rostrocaudal extent of the CAN, although their distribution pattern in the rostral CAN was different from that in the caudal CAN. Electron microscopically, serotonin-positive axonal varicosities were found to make axodendritic and axosomatic synapses on CAN neurons. Many serotonin-positive neuronal cell bodies were seen in the raphe nuclei in the lower brainstem, whereas only a few were found in the spinal cord. Thus most of serotoninergic axons within the CAN were considered to originate from the raphe nuclei in the lower brainstem. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-3940(00)00766-7

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s004419900078

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DOI： 10.1002/(SICI)1097-0185(19990101)254:1<107::AID-AR14>3.0.CO;2-Y

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/S0304-3940(98)00869-6

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DOI： 10.1016/S0165-1838(97)00099-4

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DOI： 10.1016/S0304-3940(97)00835-5

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DOI： 10.1016/S0165-1838(97)00072-6

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/0304-3940(96)12840-8

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DOI： 10.1007/s004410050571

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI PUBL IRELAND LTD  

Enzyme histochemistry combined with horseradish peroxidase retrograde tracing demonstrated NADPH-diaphorase activity in the spinal sympathetic preganglionic neurons in the spinal cord of the filefish, Stephanolepis cirrhifer; these neurons with NADPH-diaphorase activity were located just dorsal and lateral to the central canal. The results indicate that nitric oxide is synthesized in the spinal sympathetic preganglionic neurons of filefish.

DOI： 10.1016/0304-3940(95)11587-M

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Book type：Textbook, survey, introduction

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publisher：日本自律神経学会  

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Language：Japanese   Publisher：日本自律神経学会  

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Language：English   Publishing type：Research paper, summary (international conference)  

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：English   Publishing type：Research paper, summary (international conference)  

DOI： 10.1182/blood-2018-171

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Language：Japanese   Publisher：(一社)日本医学教育学会  

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Language：Japanese   Publisher：(一社)日本医学教育学会  

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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DOI： 10.1016/j.neures.2011.07.920

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本脳卒中学会  

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DOI： 10.1016/j.ijdevneu.2006.09.076

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Language：Japanese   Publisher：(一社)日本解剖学会  

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