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Objective: The Reg I gene is expressed during regeneration of various tissues but there are no studies showing its expression in skeletal muscle. The aim of our study was to explore the expression of Reg I gene in healthy skeletal muscles... more
Objective: The Reg I gene is expressed during regeneration of various tissues but there are no studies showing its expression in skeletal muscle. The aim of our study was to explore the expression of Reg I gene in healthy skeletal muscles and to define the time course of Reg I gene up- and down-regulation during muscle regeneration after muscle injury in the rat slow and fast skeletal muscle. Material and methods: In 2-month-old Wistar rats, the regeneration process was induced in slow (musculus soleus, SOL) and fast (musculus extensor digitorum longus, EDL) types of skeletal muscle. Muscle degeneration/regeneration was induced by injection of local anesthetic (0.5% bupivacain). The immunohistochemistry and western blot analysis were performed for detection and quantification of Reg I protein in regenerating skeletal muscles after 1, 2, 3, 4, 5, 6, 7, 10 and 15 days of regeneration. Results: Reg I gene was not expressed in adult, healthy SOL and EDL muscles while its expression was ...
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Research Interests: Endocrinology, Biology, Immunohistochemistry, Biological Chemistry, Medicine, and 15 moreBiological Sciences, Humans, Internal Medicine, Glucose, Insulin, Mice, Animals, CHEMICAL SCIENCES, In Vivo, Vasoactive Intestinal Peptide, Chimera, Glucose Tolerance Test, Secretion, islets of Langerhans, and Medical and Health Sciences
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Summary The regenerating gene (Reg) was isolated originally as a gene specifically over-expressed in regenerating pancreatic islets and constitute a growth factor family. Reg gene product (Reg) is important in the pathophysiology of... more
Summary The regenerating gene (Reg) was isolated originally as a gene specifically over-expressed in regenerating pancreatic islets and constitute a growth factor family. Reg gene product (Reg) is important in the pathophysiology of various human inflammatory diseases. Recently, the possible involvement of human REG in the regeneration of salivary ductal epithelial cells of patients with primary Sjögren's syndrome (SS) was reported. However, the expression of the REG family genes in minor salivary glands (MSG) and the occurrence of anti-REG Iα autoantibodies in SS patients were obscured. In this study, we examined the expression of REG family genes in the MSG of SS and screened anti-REG Iα autoantibodies in SS. The mRNA levels of REG family genes in MSG were quantified using real-time reverse transcription–polymerase chain reaction (RT–PCR) and REG Iα expression in the MSG was analysed by immunohistochemistry. The mRNA level of REG Iα in the MSG of SS patients was significantly ...
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The pathophysiology of inflammatory bowel diseases (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members (REG Iα, REG Iβ and REG IV) are expressed in Crohn's disease... more
The pathophysiology of inflammatory bowel diseases (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members (REG Iα, REG Iβ and REG IV) are expressed in Crohn's disease (CD) and ulcerative colitis (UC) and involved as proliferative mucosal factors in IBD. We revealed that REG Iα and REG Iβ were induced in cell culture system by IL‐6/IL‐22. Although REG IV was upregulated in IBD biopsy samples, the upregulation of REG IV was not at all induced in cell culture by autoimmune‐related cytokines such as IL‐6, IL‐22 and TNFα. Here, we analysed REG IV expression in LS‐174 T and HT‐29 human intestinal epithelial cells by real‐time RT–PCR and elisa. REG IV expression was induced by lipopolysaccharide (LPS). However, LPS did not activate REG IV promoter activity. As the LPS‐induced upregulation of REG IV was considered to be regulated post‐transcriptionally, we searched targeted microRNA (miR), which revealed that REG IV mRNA has a potential target sequence for miR‐24. We measured the miR‐24 level of LPS‐treated cells and found that the level was significantly lower. The LPS‐induced increase of REG IV mRNA was abolished by the introduction of miR‐24 mimic but not by non‐specific control RNA.
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Reg (regenerating gene), first isolated from a rat regenerating islet cDNA library, is expressed in regenerating islet β-cells. Recently, it has been revealed that Reg and Reg-related genes constitute a multigene family, Reg family, which... more
Reg (regenerating gene), first isolated from a rat regenerating islet cDNA library, is expressed in regenerating islet β-cells. Recently, it has been revealed that Reg and Reg-related genes constitute a multigene family, Reg family, which consists of three subtypes (type I, II, III) based on the primary structures of the encoded proteins of the genes. In mouse, type I and
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Sleep apnea syndrome (SAS), characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia (IH)), is a risk factor for hypertension and insulin resistance. We report a correlation between IH and insulin... more
Sleep apnea syndrome (SAS), characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia (IH)), is a risk factor for hypertension and insulin resistance. We report a correlation between IH and insulin resistance/diabetes. However, the reason why hypertension is induced by IH is elusive. Here, we investigated the effect of IH on the expression of catecholamine-metabolizing enzymes using an in vitro IH system. Human and mouse neuroblastoma cells (NB-1 and Neuro-2a) were exposed to IH or normoxia for 24 h. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of dopamine β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in both NB-1 and Neuro-2a. Western blot showed that the expression of DBH and PNMT in the NB-1 cells was significantly increased by IH. Reporter assays revealed that promoter activities of DBH and PNMT were not increased by IH. The miR-375 level of IH-treated cells was significantly decreased ...
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Pancreatic β-cell deficiency underlies both type 1 and type 2 diabetes, and restoration or replacement of β-cell mass/function is therefore the logical long-term solution to therapy. While it has long been held that type 1 diabetes... more
Pancreatic β-cell deficiency underlies both type 1 and type 2 diabetes, and restoration or replacement of β-cell mass/function is therefore the logical long-term solution to therapy. While it has long been held that type 1 diabetes results from an irreversible loss of β-cells, and that type 2 diabetes is primarily caused by impaired insulin action, there is now increasing evidence linking both types of diabetes to defects in β-cell mass and insulin secretion. Pancreatic β-cells have traditionally been viewed as a quiescent cell population. However, several recent lines of evidence indicated that like most tissues the β-cell mass is dramatically regulated with ongoing β-cell regeneration throughout life to replenish lost or damaged β-cells. Based on our recent data concerning β-cell death, dysfunction, and regeneration, we would like to describe regulation of pancreatic β-cell death, functioning, and regeneration.
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Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for cardiovascular disease (CVD) and insulin resistance. However, the mechanisms linking... more
Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for cardiovascular disease (CVD) and insulin resistance. However, the mechanisms linking IH stress and CVD remain elusive. We exposed rat H9c2 and mouse P19.CL6 cardiomyocytes either to sustained hypoxia (1% O2 [SH]), 70 cycles/24 h of IH (5 min SH/10 min normoxia [21% O2]), mimicking SAS patients, or normoxia for 24 h, analyzed mRNA expression and found that IH significantly increased the mRNA levels of regenerating gene (Reg) IV and hepatocyte growth factor (Hgf). Reg IV and Hgf in IH-treated cell medium were also increased. In order to analyze the IH-induced expression mechanisms of Reg IV and Hgf genes, we prepared reporter plasmids containing Reg IV and Hgf upstream of luciferase reporter gene, and transfected them into P19.CL6 cardiomyocytes. The promoter activities of the genes were not increased by IH. Target mRNA search of mic...
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Research Interests: Neuroscience and Biology
Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), and it is a known risk factor for hypertension. The upregulation of the renin-angiotensin system has been... more
Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), and it is a known risk factor for hypertension. The upregulation of the renin-angiotensin system has been reported in IH, and the correlation between renin and CD38 has been noted. We exposed human HEK293 and mouse As4.1 renal cells to experimental IH or normoxia for 24 h and then measured the mRNA levels using a real-time reverse transcription polymerase chain reaction. The mRNA levels of Renin (Ren) and Cd38 were significantly increased by IH, indicating that they could be involved in the CD38-cyclic ADP-ribose signaling pathway. We next investigated the promotor activities of both genes, which were not increased by IH. Yet, a target mRNA search of the microRNA (miRNA) revealed both mRNAs to have a potential target sequence for miR-203. The miR-203 level of the IH-treated cells was significantly decreased when compared with the normoxia-treated cells. T...
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Research Interests: Genetics, Biology, Japan, Medicine, Humans, and 15 moreInsulin, Female, Animals, Male, Clinical Sciences, Middle Aged, Glucose Transport, Public health systems and services research, Multienzyme complexes, Enzyme activity, Second Messengers, Allele Frequency, Gene frequency, Paediatrics and reproductive medicine, and In Vitro Techniques
Diabetic nephropathy is a major microvascular complication in long-standing diabetic patients who eventually undergo renal dialysis or transplantation. To prevent development of this disease and to improve advanced kidney injury,... more
Diabetic nephropathy is a major microvascular complication in long-standing diabetic patients who eventually undergo renal dialysis or transplantation. To prevent development of this disease and to improve advanced kidney injury, effective therapies directed toward the key molecular target are required. In this study, we examined whether inhibition of the receptor for advanced glycation end products (RAGE) could attenuate changes in the diabetic kidney. Here, we show that inactivation of the RAGE gene in a mouse model of diabetic nephropathy results in significant suppression of kidney changes, including kidney enlargement, increased glomerular cell number, mesangial expansion, advanced glomerulosclerosis, increased albuminuria, and increased serum creatinine compared with wild-type diabetic mice. The degree of kidney injury was proportional to RAGE gene dosage. Furthermore, we show that low–molecular weight heparin (LMWH) can bind RAGE at a mean equilibrium dissociation constant (K...
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Nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal injuries are serious clinical events and a successful therapeutic strategy is difficult. Regenerating gene (Reg) I protein functions as a regulator of cell proliferation... more
Nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal injuries are serious clinical events and a successful therapeutic strategy is difficult. Regenerating gene (Reg) I protein functions as a regulator of cell proliferation and maintains intercellular integrity in the small intestine. The aim of this study was to evaluate the role of Reg I in NSAID-induced small intestinal injuries. First, to examine the effect of Reg I deficiency on such injuries, indomethacin, a widely used NSAID, was injected subcutaneously into 10-wk-old male Reg I-knockout ( Reg I−/−) and wild-type ( Reg I+/+) mice twice with an interval of 24 h, after which the mice were euthanized. Small intestinal injuries were assessed by gross findings, histopathology, and contents of IL-1β and MPO in the experimental tissues. Next, we investigated the therapeutic potential of Reg I in indomethacin-induced small intestinal injuries. Recombinant Reg I protein (rReg I) was administered to 10-wk-old male ICR mi...
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We have recently reported that Pdx1-Cre-mediated whole pancreas inactivation of IGF-I gene [in pancreatic-specific IGF-I gene-deficient (PID) mice] results in increased β-cell mass and significant protection against both type 1 and type 2... more
We have recently reported that Pdx1-Cre-mediated whole pancreas inactivation of IGF-I gene [in pancreatic-specific IGF-I gene-deficient (PID) mice] results in increased β-cell mass and significant protection against both type 1 and type 2 diabetes. Because the phenotype is unlikely a direct consequence of IGF-I deficiency, the present study was designed to explore possible activation of proislet factors in PID mice by using a whole genome DNA microarray. As a result, multiple members of the Reg family genes (Reg2, -3α, and -3β, previously not known to promote islet cell growth) were significantly upregulated in the pancreas. This finding was subsequently confirmed by Northern blot and/or real-time PCR, which exhibited 2- to 8-fold increases in the levels of these mRNAs. Interestingly, these Reg family genes were also activated after streptozotocin-induced β-cell damage and diabetes (wild-type T1D mice) when islet cells were undergoing regeneration. Immunohistochemistry revealed incr...
Research Interests: Biology, Immunohistochemistry, Medicine, Transgenic Mice, Biological Sciences, and 11 moreMice, Female, Animals, Male, American, Type 2 Diabetes Mellitus, Experimental Diabetes Mellitus Type 1 and 2, islets of Langerhans, Gene Expression Regulation, reverse transcriptase polymerase chain reaction, and Medical and Health Sciences
Research Interests: Immunology, Flow Cytometry, Biology, Autoimmunity, Medicine, and 15 moreCell Division, Spleen, Mice, Female, Animals, Male, Peptides, Transcription Factor, Isoenzymes, Cell Proliferation, Immune Tolerance, Type 2 Diabetes Mellitus, DNA binding proteins, Glutamate decarboxylase, and islets of Langerhans
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Recently, we reported the presence of distinct cell clusters named acinar-like cell clusters touching Langerhans islets with thin interstitial surrounding (ATLANTIS) in human pancreas. A morphological study in humans demonstrated that... more
Recently, we reported the presence of distinct cell clusters named acinar-like cell clusters touching Langerhans islets with thin interstitial surrounding (ATLANTIS) in human pancreas. A morphological study in humans demonstrated that ATLANTIS and islet cell clusters are found together in the microenvironment enclosed by a common basement membrane, and ATLANTIS releases vesicles containing Regenerating gene protein (REG Iα) to islet cell clusters. We examined 1) the presence or absence of ATLANTIS in homozygous Reg I (mouse homologue of human REG Iα) deficient (Reg I) and wild-type mice, and 2) the possible role of ATLANTIS in the regeneration of beta cell clusters after encephalomyocarditis (EMC) virus (D-variant) infection in Reg I and wild-type mice. ATLANTIS was found in both wild-type and Reg I mice. In both groups, mean blood glucose increased transiently to greater than 14.0 mmol/L at 5 days after EMC virus infection and recovered to baseline at 12 days. At 12 days after EMC ...
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The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene () family members have been reported to be expressed in Crohn's disease (CD) and... more
The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene () family members have been reported to be expressed in Crohn's disease (CD) and ulcerative colitis (UC) and to be involved as proliferative mucosal factors in IBD. However, expression of allfamily genes in IBD is still unclear. Here, we analyzed expression of allfamily genes (,,,, and) in biopsy specimens of UC and CD by real-time RT-PCR.,, andgenes were overexpressed in CD samples.gene was also overexpressed in UC samples. We further analyzed the expression mechanisms of,, andgenes in human colon cells. The expression ofwas significantly induced by IL-6 or IL-22, andwas induced by IL-22. Deletion analyses revealed that three regions (- 220 to - 211, - 179 to - 156, and - 146 to - 130) inand the region (- 274 to- 260) inpromoter were responsible for the activation by IL-22/IL-6. The promoters contain consensus transcription factor b...
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The role of cyclic ADP-ribose (cADPR) and its synthetic enzyme, CD38, as a downstream signal of muscarinic acetylcholine receptors (mAChRs) was examined in neuroblastoma cells expressing M1 mAChRs (NGM1). NGM1 cells were further... more
The role of cyclic ADP-ribose (cADPR) and its synthetic enzyme, CD38, as a downstream signal of muscarinic acetylcholine receptors (mAChRs) was examined in neuroblastoma cells expressing M1 mAChRs (NGM1). NGM1 cells were further transformed with both wild-type and mutant (C119K/C201E) human CD38. The dual transformed cells exhibited higher cADPR formation than ADPR production and elevated intracellular free Ca(2+) concentrations ([Ca(2+)](i)) in response to ACh. These phenotypes were analyzed in detail in a representative CD38 clone. The intracellular cADPR concentration by ACh application was significantly increased by CD38 overexpression. Digital image analysis by a confocal microscopy revealed that topographical distribution of the sites of Ca(2+) release was unchanged between control and overexpressed cells. These results indicate that cADPR is an intracellular messenger of Ca(2+) signalling, suggesting that CD38 can contribute to mAChR-cADPR signalling.
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Cyclic ADP-ribose is generated from NAD+ in glucose-stimulated beta-cells by CD38. Cyclic ADP-ribose mobilizes Ca2+ from the endoplasmic reticulum to secrete insulin. The amino acid residues of Cys-119 and Cys-201 in CD38 are essential... more
Cyclic ADP-ribose is generated from NAD+ in glucose-stimulated beta-cells by CD38. Cyclic ADP-ribose mobilizes Ca2+ from the endoplasmic reticulum to secrete insulin. The amino acid residues of Cys-119 and Cys-201 in CD38 are essential for the synthesis and hydrolysis of cyclic ADP-ribose.