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Diabetic neuropathy is an incurable disease. We previously identified a mechanism by which aberrant bone marrow-derived cells (BMDCs) pathologically expressing proinsulin/TNF-α fuse with residential neurons to impair neuronal function. Here, we show that CD106-positive cells represent a significant fraction of short-term hematopoietic stem cells (ST-HSCs) that contribute to the development of diabetic neuropathy in mice. The important role for these cells is supported by the fact that transplantation of either whole HSCs or CD106-positive ST-HSCs from diabetic mice to non-diabetic mice produces diabetic neuronal dysfunction in the recipient mice via cell fusion. Furthermore, we show that transient episodic hyperglycemia produced by glucose injections leads to abnormal fusion of pathological ST-HSCs with residential neurons, reproducing neuropathy in nondiabetic mice. In conclusion, we have identified hyperglycemia-induced aberrant CD106-positive ST-HSCs underlie the development of diabetic neuropathy. Aberrant CD106-positive ST-HSCs constitute a novel therapeutic target for the treatment of diabetic neuropathy., Katagi et al. show that abnormal bone marrow-derived cells originated from hematopoietic stem cells (CD106-positive short-term HSCs) aberrantly fuse with neurons to develop diabetic neuropathy. This study suggests that the pathological abnormality is memorized in the bone marrow and that it cannot be erased by conventional therapy.

Background:Recently, dynamic chest radiography (DCR) was developed to evaluate pulmonary function using a flat-panel detector (FPD), which can evaluate blood flow in the pulmonary artery without injection of contrast agents. This study investigated the ability of a FPD to measure physiological changes in blood flow and to detect pulmonary embolism (PE) in monkeys., Methods and Results:DCR was performed in 5 monkeys using a FPD. Regions of interest (ROI) were placed in both lung fields of the image, and maximum changes in pixel value (∆pixel value) in the ROI were measured during 1 electrocardiogram cardiac cycle. Next, a PE model was induced using a Swan-Ganz catheter and additional images were taken. The ∆pixel value of the lungs in normal and PE models were compared in both supine and standing positions. The lung ∆pixel value followed the same cycle as the monkey electrocardiogram. ∆pixel values in the upper lung field decreased in the standing as compared to the supine position. In the PE model, the ∆pixel value decreased in the area of pulmonary blood flow occlusion and increased in the contralateral lung as compared to the normal model (normal model 1.287±0.385, PE model occluded side 0.428±0.128, PE model non-occluded side 1.900±0.431)., Conclusions:A FPD could detect postural changes in pulmonary blood flow and its reduction caused by pulmonary artery occlusion in a monkey model.

Wood creosote has been used as an herbal medicine against acute diarrhea caused by food poisoning and has an inhibitory effect on colonic motility and enterotoxin-induced ion secretion. Since no previous studies have examined the effects of wood creosote on stress-induced alteration of colonic motility, we examined the effects on the colonic motility altered by intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF), which is a key mediator in responses to stress. We recorded motor activity in proximal and distal colon of unrestrained conscious rats via two manometory catheters. The frequencies of phase III-like contraction and the % motor indices in both proximal and distal colon were measured. At the same time the number of fecal pellets excreted was counted. I.c.v. injection of CRF increased the motor activity in both proximal and distal colon, and these effects were completely antagonized by i.c.v. injection of a selective CRF type 1 antagonist but not by a CRF type 2 antagonist. Changes in colonic motility induced by CRF were reversed by intravenously administered wood creosote. Intraluminal administration of the 5-HT(3) receptor antagonist granisetron, or the 5-HT(4) receptor antagonist SB 204070 blocked the increase in colonic motility induced by i.c.v. injection of CRF. Wood creosote prevented the increase in colonic motility induced by the 5-HT(3) receptor agonist SR57227A in the proximal colon, while it prevented the increase in colonic motility induced by the 5-HT(4) receptor agonist RS67506 in the distal colon. These results indicate that wood creosote prevents the increase in colonic motility induced by CRF via 5-HT(3) receptors in the proximal colon, and via 5-HT(4) receptors in the distal colon, suggesting that wood creosote might be useful to treat stress-induced diarrhea.

Background & Aims: Although it has been shown that des-acyl ghrelin decreases food intake and gastric emptying, no previous studies have examined the effects of des-acyl ghrelin on physiologic fed and fasted motor activity in the gastrointestinal tract. Methods: We examined the effects of intraperitoneal (IP) administration of des-acyl ghrelin on food intake and the effects of intracerebroventricular (ICV) or intravenous (IV) administration of des-acyl ghrelin on gastroduodenal motility using freely moving conscious rat models. The brain nuclei responding to these effects were examined by c-fos immunohistochemistry of the brain sections. Results: IP injection of des-acyl ghrelin decreased food intake, and this effect was not altered by capsaicin treatment. IP injection of des-acyl ghrelin enhanced c-fos expression in the arcuate and paraventricular nucleus but not in the nucleus of the solitary tract. Both ICV and IV injection of des-acyl ghrelin disrupted fasted motor activity in the antrum but not in the duodenum. Changes in gastric motility induced by IV injection of des-acyl ghrelin were completely antagonized by ICV injection of a selective corticotropin-releasing factor (CRF)2 receptor antagonist; however, the CRF1 receptor antagonist had no effects. Conclusions: The results suggest that des-acyl ghrelin decreases food intake and disrupts the fasted motor activity of the antrum in freely moving conscious rats. Peripheral des-acyl ghrelin may induce this function by direct activation of brain receptor by crossing the blood-brain barrier but not by the activation of vagal afferent pathways. In the brain, CRF2 receptor, but not CRF1 receptor, is involved in this action.

Primary sensory neurons are important in regard to the initiation and propagation of intestinal inflammation. The vanilloid receptor subtype-1 (VR-1) is a cation channel located on the sensory nerves that, when stimulated, release proinflammatory peptides. Previous reports have indicated that inhibition of VR-1 with capsazepine (CPZ), a VR-1 antagonist, attenuates dextran sodium sulfate (DSS) colitis in rats. DSS-induced colitis resembles ulcerative colitis with regard to its pathologic features. In this study, we examined the effect of CPZ on trinitrobenzene sulfonic acid (TNBS)-induced colitis, an experimental model of intestinal inflammation that most closely resembles the histologic and microscopic features of Crohn's disease. Colitis was induced by administering a single enema of 100 mg/kg TNBS in 50% ethanol via catheter to lightly anesthetized rats. Subsets of rats were treated with either 1 micromol/kg/ml of CPZ or CPZ-vehicle via enema for 6 days. Seven days after TNBS administration, rats were sacrificed and inflammation was assessed using a validated macroscopic damage score (MDS) and by measuring myeloperoxidase (MPO) activity. In addition, histologic examination was performed. TNBS administration resulted in reproducible chronic erosive lesions extending into the muscularis propria and extensive recruitment of neutrophils in the distal colon. MDS and MPO scores were considerably elevated in the TNBS colons when compared with the TNBS vehicle animals. TNBS rats treated with CPZ enemas exhibited a substantial reduction in MDS and MPO scores and demonstrated dramatically improved pathologic findings. Topical CPZ resulted in considerable attenuation of TNBS-induced colitis. These results support the role of VR-1 and sensory neurons with regard to intestinal inflammation.

Dysregulated metabolism and consequent extracellular accumulation of amyloid-β (Aβ) peptides in the brain underlie the pathogenesis of Alzheimer's disease. Extracellular Aβ in the brain parenchyma is mainly secreted from the pre-synaptic terminals of neuronal cells in a synaptic activity-dependent manner. The p24 family member p24α2 reportedly attenuates Aβ generation by inhibiting γ-secretase processing of amyloid precursor protein; however, the pattern of expression and localization of p24α2 in the brain remains unknown. We performed immunohistochemical staining and subcellular fractionation for p24α2 in the mouse brain. Immunostaining showed that p24α2 is broadly distributed in the gray matter of the central nervous system and is predominantly localized to synapses. Subcellular fractionation revealed prominent localization of p24α2 in the pre-synaptic terminals. Immunoisolation of synaptic vesicles (SV) indicated that p24α2 is condensed at active zone-docked SV. During development, p24α2 expression is highest in the post-natal period and gradually decreases with age. We also confirmed that amyloid precursor protein and γ-secretase components are localized at active zone-docked SV. Our results suggest a novel functional role for p24α2 in the regulation of synaptic transmission and synaptogenesis, and provide evidence for the participation of p24α2 in the regulation of Aβ generation and secretion in the brain. The p24 family member p24α2 attenuates amyloid-β (Aβ) generation by inhibiting the γ-secretase processing. We report that p24α2 is condensed at active zone-docked synaptic vesicles in the brain. p24α2 expression is highest in the post-natal period and gradually decreases with age. Our results suggest a novel function for p24α2 at the synapse, including the regulation of brain Aβ generation.

Brain-derived neurotrophic factor (BDNF) suppresses food intake by acting on neurons in the hypothalamus. Here we show that BDNF-producing haematopoietic cells control appetite and energy balance by migrating to the hypothalamic paraventricular nucleus. These haematopoietic-derived paraventricular nucleus cells produce microglial markers and make direct contacts with neurons in response to feeding status. Mice with congenital BDNF deficiency, specifically in haematopoietic cells, develop hyperphagia, obesity and insulin resistance. These abnormalities are ameliorated by bone marrow transplantation with wild-type bone marrow cells. Furthermore, when injected into the third ventricle, wild-type bone marrow mononuclear cells home to the paraventricular nucleus and reverse the hyperphagia of BDNF-deficient mice. Our results suggest a novel mechanism of feeding control based on the production of BDNF by haematopoietic cells and highlight a potential new therapeutic route for the treatment of obesity. Brain-derived neurotrophic factor is produced in the brain and is a known regulator of energy homoeostasis. Here Urabe and colleagues show that brain-derived neurotrophic factor-producing haematopoietic cells control appetite by migrating into the hypothalamus, where they make contact with neurons.

Cancer cachexia is reported to be a major cause of cancer-related death. Since the pathogenesis is not entirely understood, only few effective therapies have been established. Since myriad tumors produce parathyroid hormone-related protein (PTHrP), plasma concentrations of PTHrP are increased in cancer cachexia. We measured the food intake, gastric emptying, conditioned taste aversion (CTA), and gene expression of hypothalamic neuropeptides in mice after administering PTHrP intraperitoneally. We administered PTHrP intravenously in rats and examined the gastroduodenal motility and vagal nerve activities. We also examined whether chronic administration of PTHrP influenced the food intake and body weight. Peripherally administered PTHrP induced negative energy balance by decreasing the food intake and gastric emptying; however, it did not induce CTA. The mechanism involved the activation of hypothalamic urocortins 2 and 3 through vagal afferent pathways and the suppression of gastroduodenal motor activity. The continuous infusion of PTHrP reduced the food intake and body weight gain with a concomitant decrease in the fat and skeletal muscle. Our findings suggest that PTHrP influences the food intake and body weight; therefore, PTHrP can be considered as a therapeutic target for cancer cachexia.

Objective: To evaluate the role of transient receptor potential vanilloid 1 (TRPV1) in a rat hemorrhagic shock (HS) model using the TRPV1 antagonist, capsazepine (CPZ). Summary Background Data: TRPV1, distributed within the sensory nerve, plays a role in the regulation of cardiovascular functions. TRPV1 may be involved in the cardiovascular responses to HS. Methods: Male rats were anesthetized and HS was induced with the mean arterial pressure (MAP) at 30 mm Hg for 90 minutes. CPZ (5.0 mol/kg) was administered at 30 minutes after the shock induction, and the 24-hour survival rates were assessed. The MAP, heart rate, and shed blood volume (SBV) were recorded throughout the experiment. Arterial blood gas analysis and the plasma catecholamines levels were measured before and after HS. Double-immunohistochemistry for Fos and tyrosine hydroxylase (TH) was performed in the rostral ventrolateral medulla (RVLM) of the brain. Results: CPZ significantly improved the 24-hour survival rates, which was accompanied by the increase in the MAP and the SBV, a decrease of the plasma catecholamines levels, and attenuation of the severe metabolic acidosis. Furthermore, CPZ reduced the percentage of double-labeled neurons for Fos and TH in the RVLM of the rat brain. Conclusions: TRPV1 may be involved in the regulation of the cardiovascular responses to HS, at least in part, by recruiting catecholaminergic neurons in the RVLM. CPZ appears to induce metabolic compensations, which may be potentially useful in HS.

Background and aims: The role of sensory neurones in colitis was studied by chemical denervation of primary sensory neurones as well as antagonism of the vanilloid receptor-1 (VR-1) in rats prior to administration of dextran sulphate sodium (DSS) to induce colitis. Methods: Neonatal rats were chemically denervated by subcutaneous administration of capsaicin; controls received capsaicin vehicle only. When animals reached maturity, colitis was induced by administration of 5% DSS in drinking water for seven days. Additionally, normal adult rats were treated with a VR-1 antagonist capsazepine (CPZ) or vehicle twice daily via an enema from day 0 to day 6 of the DSS regimen. Control rats were treated with an enema infusion of vehicle and 5% DSS, or without either an enema infusion or DSS in drinking water. For both groups of rats, severity of inflammation was quantitated by disease activity index (DAI), myeloperoxidase (MPO) activity, and histological examination. Results: DSS induced active colitis in all control rats with resultant epithelial ulceration, crypt shortening, and neutrophil infiltration. Both neonatal capsaicinised rats and normal adult rats treated with CPZ enemas exhibited significantly lower levels of DAI, MPO, and histological damage compared with vehicle treated rats (p Conclusions: Neonatal capsaicinisation and local administration of CPZ prevents intestinal inflammation in a well established model of colitis indicating that primary sensory neurones possessing VR-1 receptors are required in the propagation of colonic inflammation.