Comparison of physiological functions between neuromedin U-related peptide and neuromedin S-related peptide in the rat central nervous system.

Two novel peptides, neuromedin U precursor-related peptide (NURP) and neuromedin S precursor-related peptide (NSRP), are produced from neuromedin U (NMU) and neuromedin S (NMS) precursors, respectively, as these precursors have multiple consensus sequences for proteolytic processing. Our group has shown previously that one of these two novel peptides, NURP, stimulates body temperature and locomotor activity, but not food intake. However, the physiological function of the other peptide, NSRP, has remained unclear. Therefore, the aim of this study was to characterize differences in the regions of the rat brain targeted by the NMU/NMS peptide family, including NURP and NSRP, and their physiological functions. First, we explored the regions of c-Fos expression after intracerebroventricular (i.c.v.) injection of NURP and NSRP and found that these were fewer than after i.c.v. injection of NMU and NMS in the hypothalamus, possibly because NURP and NSRP cannot activate NMU/NMS receptors. In the ventral subiculum, which is one region of the hippocampus, c-Fos expression was evident only after i.c.v. injection of NURP. We also examined the effects of NSRP on food intake, body temperature and locomotor activity. Like NURP, NSRP increased both body temperature and locomotor activity, but not food intake, indicating that NSRP is also a functional peptide. However, these effects of NSRP were distinctly weaker than those of NURP. These findings suggest differences in the affinity of NURP and/or NSRP for specific receptors, or in their respective biological activities.

Is using intracerebral hemorrhage scoring systems valid for mortality prediction in surgically treated patients?

While intracerebral hemorrhage (ICH) scoring systems provide mortality and morbidity prediction, the actual mortality rates seem to be lower than those predicted by scoring systems in our clinical impression. To assess the validity of the ICH score and the Surgical Swedish ICH (SwICH) score, we retrospectively reviewed surgically treated ICH patients between 2012 and 2019. Uni- and multivariate analyses were performed to identify variables in predicting 30-day mortality. We identified 203 patients (mean ICH score 2.7; mean SwICH score 2.0). The actual 30-day mortality was 7%, which was significantly lower than those predicted by the ICH and the SwICH scores (55% and 16%, respectively; p < 0.001). Both scores were strongly correlated with the modified Rankin scale (mRS) at discharge (correlation coefficient 0.97 and 0.98; critical value 0.81). The only significant prognostic factors for the 30-day mortality by multivariate analysis were anisocoria (p = 0.03) and preoperative Glasgow Coma Scale (p = 0.03). These two factors also predicted mRS at discharge (p < 0.001). After discharge, 15% of patients improved regarding mRS and 29% of wheelchair-bound patients gained the ability to ambulate. No significant relationship existed between the degree of recovery after discharge and preoperative ICH score (p = 0.25). The ICH and SwICH scores were more valid in predicting morbidity, rather than mortality after surgical intervention for ICH. Anisocoria and Glasgow Coma Scale < 7 were the only two factors that predicted 30-day mortality and morbidity at discharge.

Neuromedin U suppresses prolactin secretion via dopamine neurons of the arcuate nucleus.

Neuromedin U (NMU) has a precursor that contains one additional peptide consisting of 33 or 36 amino acid residues. Recently, we identified this second peptide from rat brain and designated it neuromedin U precursor-related peptide (NURP), showing it to stimulate prolactin release from the pituitary when injected via the intracerebroventricular (icv) route. Here, we examined whether NMU, like NURP, also stimulates prolactin release. Unlike NURP, icv injection of NMU significantly decreased the secretion of prolactin from the pituitary. This suppression of prolactin release by NMU was observed in hyper-prolactin states such as lactation, stress, pseudopregnancy, domperidone (dopamine antagonist) administration, and icv injection of NURP. Immunohistochemical analysis revealed that icv injection of NMU induced cFos expression in dopaminergic neurons of the arcuate nucleus, but not the substantia nigra. Mice with double knockout of NMU and neuromedin S (NMS), the latter also binding to NMU receptors, showed a significant increase of the plasma prolactin level after domperidone treatment relative to wild-type mice. These results suggest that NMU and NURP may play important reciprocal roles in physiological prolactin secretion.

Guest Vapor-Induced State Change of Structural Liquid Pillar[6]arene.

State change is a key phenomenon in materials science. We report the first observation of vapor-responsive reversible structural liquid-to-solid and solid-to-structural liquid state changes. We observed that a macrocyclic compound, a pillar[6]arene derivative bearing 12 n-hexyl substituents, is a room temperature structural liquid with unique properties. Formation of a host-guest complex between the pillar[6]arene cavity and the n-hexyl substituent results in a structural liquid with nanoscale structural heterogeneities. The structural liquid solidifies when exposed to competitive cyclohexane guest vapor, whereupon cyclohexane replaces the n-hexyl substituents in the pillar[6]arene cavity and the n-hexyl substituents located outside of the cavity crystallize into distinct nanolayer assemblies. The solid reverts back to the structural liquid when the cyclohexane guest is removed through heating under reduced pressure because of rethreading of the n-hexyl substituents into the cavity. The structural liquid-to-solid and solid-to-structural liquid changes are reversible through the uptake and release of cyclohexane guest vapor.

Purification and identification of native forms of goldfish neuromedin U from brain and gut.

Neuromedin U (NMU) plays important roles in energy homeostasis in rodents and birds. Previously, our group has isolated four cDNAs encoding precursor proteins of NMU from the goldfish brain and gut, and it was assumed that these transcripts are produced by alternative splicing. We have also demonstrated that intracerebroventricular (ICV) injection of putative goldfish NMU inhibits food intake. However, as native goldfish NMU has not yet been identified, we attempted to purify it from goldfish brain and gut extracts. To assess NMU activity in fractions at each purification step, we measured changes in the intracellular concentrations of Ca2+ using HEK293 cells expressing goldfish NMU-R1 or -R2. We isolated a 25-amino-acid peptide (NMU-25) from the brain and gut and found that its primary structure is similar to that of mammalian NMU. Another 21-amino-acid peptide (NMU-21) was purified from the brain, but not from the gut. Furthermore, a 9-amino-acid peptide (NMU-9) identical to the C-terminus of NMU-21 and -25 was also isolated from the brain and gut. Treatment with synthetic NMU-9, -21 and -25 dose-dependently increased the intracellular Ca2+ concentration in mammalian cells expressing goldfish NMU-R1 and -R2. We also examined the effect of ICV-administered synthetic goldfish NMUs on goldfish food intake. NMU-25 inhibited food intake to the same degree as NMU-21. However, the inhibitory effect of NMU-9 was slightly weaker than those of NMU-21 and -25. These results indicate that several molecular forms of NMU exist in the goldfish brain and gut, and that all of them play physiological roles via NMU-R1 and NMU-R2.

Novel Detection of CALR-Mutated Cells in Myeloproliferative Neoplasm-Related Glomerulopathy With Interstitial Extramedullary Hematopoiesis: A Case Report.

Myeloproliferative neoplasms (MPNs) are associated with somatic mutations of genes including JAK2, CALR, or MPL in hematopoietic stem cells. Various glomerular lesions are known to be involved in MPN-related glomerulopathy, including mesangial hypercellularity, segmental sclerosis, features of chronic thrombotic microangiopathy, and intracapillary hematopoietic cell infiltration. Renal extramedullary hematopoiesis (EMH) is uncommon, but it is reported to occur in the setting of MPN; however, to our knowledge, there have been no reports of renal EMH with pathologically verified mutations. We report the case of a 65-year-old woman with MPN who had a CALR mutation and developed nephrotic syndrome. Kidney biopsy showed the typical findings of MPN-related glomerulopathy. CALR mutation-specific immunostaining of the kidney revealed immunopositive cells in the EMH lesion of the interstitium, indicating that renal EMH was caused by CALR-mutated cells. Based on these findings, we diagnosed nephrotic syndrome caused by MPN-related glomerulopathy. After initiation of steroid therapy, the patient's proteinuria gradually decreased and she achieved an incomplete remission. Additionally, the patient was prescribed the JAK inhibitor ruxolitinib and maintained incomplete remission. There is no established treatment for MPN-related glomerulopathy; therefore, further studies are needed to elucidate its pathophysiology.

Pericyte-Specific Ninjurin1 Deletion Attenuates Vessel Maturation and Blood Flow Recovery in Hind Limb Ischemia.

Objective- Angiogenesis, entire step from endothelial cells (ECs) sprouts to vascular maturation, is a critical response to ischemia. To form functional mature vessels, interactions between ECs and pericytes are essential. Ninj1 (ninjurin1) is an adhesion molecule that contributes to the pathogenesis of neuroinflammation. We recently demonstrated that Ninj1 is expressed in pericytes during angiogenesis. However, the role of Ninj1 in angiogenesis under pathophysiological ischemic conditions has not yet been elucidated. Approach and Results- Ninj1 was detected in microvessels, and its expression was enhanced in ischemic tissues after mouse hindlimb ischemia. Knockdown of Ninj1 was performed by injection of biodegradable microspheres releasing Ninj1-small interfering RNA into muscle tissues. Alternatively, pericyte-specific Ninj1 knockout was induced by tamoxifen treatment of NG2-CreERT/Ninj1-flox mice. Ninj1 knockdown/knockout reduced the formation of blood-circulating functional vessels among total CD31+ microvessels within ischemic tissues and subsequently attenuated color Doppler-assessed blood flow recovery. Ninj1 overexpression enhanced expression of Anpt (angiopoietin) 1, whereas Ninj1 knockdown enhanced the endogenous Anpt1 antagonist, Anpt2 expression in pericytes and inhibited the association of pericytes with ECs and subsequent formation of capillary-like structure, that is, EC tube surrounded with pericytes in 3-dimensional gel culture. Conclusions- Our data demonstrate that Ninj1 is involved in the formation of functional matured vessels through the association between pericytes and ECs, resulting in blood flow recovery from ischemia. These findings further the current our understanding of vascular maturation and may support the development of therapeutics for ischemic diseases.

Metallonanobelt: A Kinetically Stable Shape-Persistent Molecular Belt Prepared by Reversible Self-Assembly Processes.

A triptycene-based shape-persistent belt-shaped macrocycle, metallonanobelt, was synthesized by the self-assembly of 2,3,6,7-tetraaminotriptycene L and square planar Pd2+. The pentamer was selectively formed by the complexation of L with Pd2+ in the presence of the pillar[6]arene derivative P6 having triethylene glycol pendant as a template, whereas a mixture of a trimer, tetramer, and pentamer was obtained in the absence of the template. The pentamer was successfully isolated based on the solubility difference between the metallonanobelt and the template. It was also revealed that the isolated pentamer was remarkably stable in solutions such as acetonitrile or methanol thanks to the relatively inert planar chelate metal complex, [Pd( o-phenylenediamine)2] unit. Thus, we can handle the metallonanobelt almost as a static organic nanobelt that is synthesized covalently.

Malnutrition Increases the Incidence of Death, Cardiovascular Events, and Infections in Patients with Stroke after Rehabilitation.

BACKGROUND: Although the impact of malnutrition in patients with acute stroke has been reported, its significance after rehabilitation is not well understood. The geriatric nutritional risk index (GNRI) is a simple and well-established nutritional screening tool that predicts poor prognosis in elderly patients and in those with a high risk of cardiovascular events. We investigated the associations between GNRI and all-cause mortality, cardiovascular events, and infectious diseases in patients with stroke after rehabilitation. METHODS: This study included 138 patients aged 80 years or below who were discharged between 2010 and 2013 in a single center, and followed up for more than 1 year. Malnutrition was defined as a GNRI of 96 or lower. RESULTS: The mean age was 63.9 ± 11.0 years, the mean GNRI at discharge was 98.8 ± 6.5, and the mean total functional independence measure (FIM) score at discharge was 91.8 ± 25.8. Among the patients, 37 (27%) had malnutrition. During the follow-up period, all-cause mortality, cardiovascular events, and infectious diseases were recorded in 11 (8%), 21 (15%), and 20 (15%) patients, respectively. Kaplan-Meier curves showed a significantly higher incidence of each outcome in patients with a GNRI of 96 or lower. In the Cox proportional analysis, GNRI was an independent determinant of all-cause mortality (hazard ratio [HR], .71; 95% confidence interval [CI], .61-.83), cardiovascular events (HR, .87; 95% CI, .80-.95), and infectious diseases (HR, .80; 95% CI, .74-.87) after adjusting for age, gender, and total FIM score. CONCLUSIONS: Malnutrition has a negative impact on prognosis in patients with stroke even after rehabilitation.

Neuromedin U precursor-related peptide (NURP) exerts neuromedin U-like sympathetic nerve action in the rat.

It has been suggested that novel peptide that is produced from the neuromedin U (NMU) precursor may exist, as this precursor contains multiple consensus sequences for proteolytic processing. Recently, we identified two mature novel peptides comprising 33 and 36 residues in the rat brain, which were designated neuromedin U precursor-related peptide (NURP) 33 and 36. In the present study, we compared the roles of NURP33 and 36 with that of NMU, as neither activates the NMU receptors. Immunoreactivity for NMU and NURPs was widely present in the central nervous system and showed a similar distribution. Intracerebroventricular (icv) injection of NURP33 in rats increased locomotor activity, energy expenditure, heart rate and back surface temperature (BS-T), similarly to NMU or NURP36. NMU treatment reduced food intake, but NURP33 did not. Pretreatment with the ß3 blocker, SR59230A, and the cyclooxygenase blocker, indomethacin, inhibited the NURP33- or NMU-induced increase of BS-T. In addition, icv injection of NURP33 or NMU increased the expression of mRNA for cyclooxygenase 2 in the hypothalamus and for uncoupling protein 1 in the brown adipose tissue. These results suggest that although NURP33 and 36 do not activate the NMU receptors, they might exert NMU-like sympathetic nerve action in the brain.

Relationship between intracranial aneurysms and the severity of autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disease characterized by the progressive enlargement of innumerable renal cysts. Although the association of intracranial aneurysms (ICANs) with ADPKD is well known, the relationship between the ICAN and the disease severity including total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) is poorly understood. METHODS: We screened 265 patients with ADPKD (mean age, 48.8 years; range, 14.9-88.3 years) with MR angiography. The patients with a past history related to ICANs were excluded from the study. The incidence and characteristics of ICAN in patients with ADPKD were evaluated. TKV was measured by volumetric analyses of MR imaging. RESULTS: We detected 65 ICANs in 49 patients (37 women and 12 men, mean age, 52.7 years; range, 20.4-86 years). The incidence of ICANs was 18.5% and female patients had was higher incidence (23.1%) than male patients (11.4%) (p = 0.02). An age of those with ICANs was significantly higher than those without (p = 0.006), and the cumulative risk of diagnosis of ICANs increased with age. TKV was significantly larger in those with ICANs than those without (p = 0.001), but eGFR was not different between two groups (p = 0.07). By multivariate analyses, only TKV was significantly related to the development of ICANs (p = 0.02). CONCLUSIONS: The incidence of ICANs increased with age, was higher in females, and correlated with kidney enlargement in patients with ADPKD. Necessity of screening ICANs would be particularly high in elderly women with large kidneys.

Black hairy tongue after chemotherapy for malignant brain tumors.

Black hairy tongue (BHT) developed in five patients (2.6%) among 192 patients undergoing chemotherapy for malignant brain tumors. Three patients with a history of diabetes mellitus developed BHT within 10 days after the initiation of chemotherapy. The other two patients suffered more than 100 days after induction and lymphopenia of grade 3 or worse developed for more than 20 days, which was not observed in the three patients with diabetes. We found that BHT could develop after chemotherapy for malignant brain tumors. Patients with diabetes mellitus presented early after chemotherapy, while patients with longstanding severe lymphopenia presented in late phase.

Hemocholecyst complicated in a hemodialysis patient with microscopic polyangiitis.

Microscopic polyangiitis (MPA) is a systemic vasculitis associated with antineutrophil cytoplasmic antibodies, and it involves multiple organs, including the kidneys and lungs. We report on the case of a 72-year-old woman with MPA who developed hemocholecyst in addition to alveolar hemorrhage and rapidly progressive glomerulonephritis. Although her renal function was not salvaged, the alveolar hemorrhage and hemocholecyst were treated conservatively. Clinicians should consider the possibility of hemocholecyst in patients with MPA complaining of abdominal pain.

Successful percutaneous transluminal angioplasty for the treatment of renovascular hypertension with an atrophic kidney.

Renovascular hypertension is an important cause of secondary hypertension. We present the case of a 61-year-old man with renovascular hypertension caused by chronic total occlusion of the left renal artery resulting in an atrophic kidney. Although renography indicated almost no residual function of the left kidney, renal vein sampling showed a significant increase of renin secretion in the left kidney. The endocrine function of the left kidney was believed to be preserved; thus, we performed percutaneous transluminal renal angioplasty with stent placement. After the procedure, the patient's blood pressure decreased gradually to within the normal range without adverse events. The laboratory data on endocrine function and the renography findings drastically improved. Percutaneous transluminal renal angioplasty is a promising therapeutic procedure for renovascular hypertension with an atrophic kidney.

Successful treatment of coexisting membranous nephropathy and immune thrombocytopenia by eradicating gastric Helicobacter pylori infection: a case report.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in middle-aged and older adults. MN etiology is mainly primary or idiopathic; however, it may also be secondary to infections, drugs, neoplasms, and autoimmune diseases. We present the case of a 52-year-old Japanese man with coexisting nephrotic MN and immune thrombocytopenic purpura (ITP). Renal biopsy revealed glomerular basement membrane thickening with immunoglobulin (Ig) G and complement component 3 deposition. Glomerular IgG subclass analysis revealed predominant IgG4 deposition with weak IgG1 and IgG2 deposition. IgG3 and phospholipase A2 receptor deposits were negative. Upper endoscopy revealed no ulcers, but histological examination demonstrated Helicobacter pylori infection in the gastric mucosa with elevated IgG antibodies. After gastric Helicobacter pylori eradication, the nephrotic-range proteinuria and thrombocytopenia of the patient were markedly improved without initiation of immunosuppressive treatment. Therefore, clinicians should consider the possibility of Helicobacter pylori infection in patients with coexisting MN and ITP. Further studies are required to demonstrate the associated pathophysiological aspects.

Outcome of Visual Function after Removal of Tuberculum Sellae Meningioma Presenting with Scotoma at the Lower Visual Field Center.

Tuberculum sellae meningiomas commonly present as bitemporal hemianopia and loss of visual acuity due to optic nerve compression. Two female patients (48 and 58 years old) presented with a small scotoma at the lower visual field center due to tuberculum sellae meningioma (25 and 10 mm, respectively). Despite the fact that their visual field defect was not very large, daily activities, including walking or reading were hindered. By the total removal of the tumors in both patients, the scotoma was cured and daily activities recovered. When patients exhibit visual deficits, especially in the lower center fields, surgical removal should be considered even if the tumors are small and visual deficits are limited because improvement of both vision and daily activities can be achieved.

Inducible deletion of microRNA activity in kidney mesenchymal cells exacerbates renal fibrosis.

MicroRNAs (miRNAs) are sequence-specific inhibitors of post-transcriptional gene expression. However, the physiological functions of these non-coding RNAs in renal interstitial mesenchymal cells remain unclear. To conclusively evaluate the role of miRNAs, we generated conditional knockout (cKO) mice with platelet-derived growth factor receptor-ß (PDGFR-ß)-specific inactivation of the key miRNA pathway gene Dicer. The cKO mice were subjected to unilateral ureteral ligation, and renal interstitial fibrosis was quantitatively evaluated using real-time polymerase chain reaction and immunofluorescence staining. Compared with control mice, cKO mice had exacerbated interstitial fibrosis exhibited by immunofluorescence staining and mRNA expression of PDGFR-ß. A microarray analysis showed decreased expressions of miR-9-5p, miR-344g-3p, and miR-7074-3p in cKO mice compared with those in control mice, suggesting an association with the increased expression of PDGFR-ß. An analysis of the signaling pathways showed that the major transcriptional changes in cKO mice were related to smooth muscle cell differentiation, regulation of DNA metabolic processes and the actin cytoskeleton, positive regulation of fibroblast proliferation and Ras protein signal transduction, and focal adhesion-PI3K/Akt/mTOR signaling pathways. Depletion of Dicer in mesenchymal cells may downregulate the signaling pathway related to miR-9-5p, miR-344g-3p, and miR-7074-3p, which can lead to the progression of chronic kidney disease. These findings highlight the possibility for future diagnostic or therapeutic developments for renal fibrosis using miR-9-5p, miR-344g-3p, and miR-7074-3p.

Characterization of a novel genetically obese mouse model demonstrating early onset hyperphagia and hyperleptinemia.

Obesity is a critical risk factor for the development of metabolic syndrome, and many obese animal models are used to investigate the mechanisms responsible for the appearance of symptoms. To establish a new obese mouse model, we screened ∼13,000 ICR mice and discovered a mouse demonstrating spontaneous obesity. We named this mouse "Daruma" after a traditional Japanese ornament. Following the fixation of the genotype, these animals exhibited obese phenotypes according to Mendel's law of inheritance. In the Daruma mouse, the leptin receptor gene sequence carried two base mutations that are good candidates for the variation(s) responsible for the obese phenotype. The Daruma mice developed characteristic visceral fat accumulation at 4 wk of age, and the white adipose and liver tissues exhibited increases in cell size and lipid droplets, respectively. No histological abnormalities were observed in other tissues of the Daruma mice, even after the mice reached 25 wk of age. Moreover, the onset of impaired leptin signaling was early and manifested as hyperleptinemia and hyperinsulinemia. Pair feeding completely inhibited obesity, although these mice rapidly developed hyperphagia and obesity followed by hyperleptinemia when pair feeding ceased and free-access feeding was permitted. Therefore, the Daruma mice exhibited unique characteristics and may be a good model for studying human metabolic syndrome.

Central and peripheral des-acyl ghrelin regulates body temperature in rats.

In the present study using rats, we demonstrated that central and peripheral administration of des-acyl ghrelin induced a decrease in the surface temperature of the back, and an increase in the surface temperature of the tail, although the effect of peripheral administration was less marked than that of central administration. Furthermore, these effects of centrally administered des-acyl ghrelin could not be prevented by pretreatment with [D-Lys3]-GHRP-6 GH secretagogue receptor 1a (GHS-R1a) antagonists. Moreover, these actions of des-acyl ghrelin on body temperature were inhibited by the parasympathetic nerve blocker methylscopolamine but not by the sympathetic nerve blocker timolol. Using immunohistochemistry, we confirmed that des-acyl ghrelin induced an increase of cFos expression in the median preoptic nucleus (MnPO). Additionally, we found that des-acyl ghrelin dilated the aorta and tail artery in vitro. These results indicate that centrally administered des-acyl ghrelin regulates body temperature via the parasympathetic nervous system by activating neurons in the MnPO through interactions with a specific receptor distinct from the GHS-R1a, and that peripherally administered des-acyl ghrelin acts on the central nervous system by passing through the blood-brain barrier, whereas it exerts a direct action on the peripheral vascular system.

Structure-activity relationships of bisphenol A analogs at estrogen receptors (ERs): discovery of an ERα-selective antagonist.

Our multi-template approach for drug discovery, focusing on protein targets with similar fold structures, has yielded lead compounds for various targets. We have also shown that a diphenylmethane skeleton can serve as a surrogate for a steroid skeleton. Here, on the basis of those ideas, we hypothesized that the diphenylmethane derivative bisphenol A (BPA) would bind to the ligand-binding domain of estrogen receptors (ERs) in a similar manner to estradiol and act as a steroid surrogate. To test this idea, we synthesized a series of BPA analogs and evaluated their structure-activity relationships, focusing on agonistic/antagonistic activities at ERs and ERα/ERß subtype selectivity. Among the compounds examined, 18 was found to be a potent ERα-antagonist with high selectivity over ERß and androgen receptor under our assay conditions. A computational docking study suggested that 18 would bind to the antagonistic conformation of ERα. ERα-selective antagonists, such as 18, are candidate agents for treatment of breast cancer.