Publications by authors named "Kazuhiro Kimura"

210 Publications

Melanin-concentrating hormone-producing neurons in the hypothalamus regulate brown adipose tissue and thus contribute to energy expenditure.

J Physiol 2021 Apr 26. Epub 2021 Apr 26.

Laboratory of Biochemistry, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan.

Key Points: MCH neuron-ablated mice exhibit increased energy expenditure and reduced fat weight. Increased BAT activity and locomotor activity-independent energy expenditure contributed to body weight reduction in MCH neuron-ablated mice. MCH neurons send inhibitory input to the medullary raphe nucleus to modulate BAT activity.

Abstract: Hypothalamic melanin-concentrating hormone (MCH) peptide robustly affects energy homeostasis. However, it is unclear whether and how MCH-producing neurons, which contain and release a variety of neuropeptides/transmitters, regulate energy expenditure in the central nervous system and peripheral tissues. We thus examined the regulation of energy expenditure by MCH neurons, focusing on interscapular brown adipose tissue (BAT) activity. MCH neuron-ablated mice exhibited reduced body weight, increased oxygen consumption, and increased BAT activity, which improved locomotor activity-independent energy expenditure. Trans-neuronal retrograde tracing with the recombinant pseudorabies virus revealed that MCH neurons innervate BAT via the sympathetic premotor region in the medullary raphe nucleus (MRN). MRN neurons were activated by MCH neuron ablation. Therefore, endogenous MCH neuron activity negatively modulates energy expenditure via BAT inhibition. MRN neurons might receive inhibitory input from MCH neurons to suppress BAT activity. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1113/JP281241DOI Listing
April 2021

Prostaglandin in the ventromedial hypothalamus regulates peripheral glucose metabolism.

Nat Commun 2021 04 20;12(1):2330. Epub 2021 Apr 20.

Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.

The hypothalamus plays a central role in monitoring and regulating systemic glucose metabolism. The brain is enriched with phospholipids containing poly-unsaturated fatty acids, which are biologically active in physiological regulation. Here, we show that intraperitoneal glucose injection induces changes in hypothalamic distribution and amounts of phospholipids, especially arachidonic-acid-containing phospholipids, that are then metabolized to produce prostaglandins. Knockdown of cytosolic phospholipase A2 (cPLA2), a key enzyme for generating arachidonic acid from phospholipids, in the hypothalamic ventromedial nucleus (VMH), lowers insulin sensitivity in muscles during regular chow diet (RCD) feeding. Conversely, the down-regulation of glucose metabolism by high fat diet (HFD) feeding is improved by knockdown of cPLA2 in the VMH through changing hepatic insulin sensitivity and hypothalamic inflammation. Our data suggest that cPLA2-mediated hypothalamic phospholipid metabolism is critical for controlling systemic glucose metabolism during RCD, while continuous activation of the same pathway to produce prostaglandins during HFD deteriorates glucose metabolism.
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http://dx.doi.org/10.1038/s41467-021-22431-6DOI Listing
April 2021

Effect of 5-azacytidine (5-aza) on UCP2 expression in human liver and colon cancer cells.

Int J Med Sci 2021 19;18(10):2176-2186. Epub 2021 Mar 19.

College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea.

The function of the uncoupling protein 2 (UCP2) is different for each cancer cell. However, the mechanism of expression is still unclear. DNA methylation affects protein expression and is one factor that transforms normal cells into cancer cells. In this study, the hepatocellular carcinoma Hep3B and HepG2 cells and colorectal cancer HT-29 cells were treated with 5-azacytidine (5-aza), a DNA demethylation agent, to observe the modification of UCP2 expression and the methylation degree in the UCP2 promoter region. Promoter basal activity and degree of UCP2 expression were measured in Hep3B, HepG2, and HT-29 cells. In addition, methylation-specific PCR (MSP) was performed to investigate the degree of methylation in the UCP2 promoter region. The methylation region in the UCP2 promoter was confirmed based on bisulfite sequencing. In Hep3B cells in which UCP2 mRNA was not transcribed, the promoter basal activity was significantly higher than in HT-29 or HepG2 cells in which UCP2 mRNA was transcribed. Treatment with 5-aza increased UCP2 expression in Hep3B and HT-29 cells; however, the expression in HepG2 cells was unchanged. The UCP2 promoter in Hep3B cells has numerous methylated regions compared with HT-29 and HepG2 cells. The results of the present study revealed that inhibition of UCP2 expression in Hep3B cells was due to methylation of the promoter region. Investigating the mechanism that induces UCP2 expression in cancer cells is important to understand the function of UCP2, which could aid in cancer treatment.
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http://dx.doi.org/10.7150/ijms.56564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040421PMC
March 2021

Clinical Characteristics and Outcomes in 314 Japanese Patients with Bacterial Endophthalmitis: A Multicenter Cohort Study from J-CREST.

Pathogens 2021 Mar 24;10(4). Epub 2021 Mar 24.

Department of Ophthalmology, Hyogo College of Medicine, Nishinomiya 6638501, Japan.

Bacterial endophthalmitis is an intraocular infection that causes rapid vison loss. Pathogens can infect the intraocular space directly (exogenous endophthalmitis (ExE)) or indirectly (endogenous endophthalmitis (EnE)). To identify predictive factors for the visual prognosis of Japanese patients with bacterial endophthalmitis, we retrospectively examined the bacterial endophthalmitis characteristics of 314 Japanese patients and performed statistics using these clinical data. Older patients, with significantly more severe clinical symptoms, were prevalent in the ExE group compared with the EnE group. However, the final best-corrected visual acuity (BCVA) was not significantly different between the ExE and EnE groups. Bacteria isolated from patients were not associated with age, sex, or presence of eye symptoms. , and were more prevalent in ExE patients than EnE patients and contributed to poor final BCVA. The presence of eye pain, bacterial identification, and poor BCVA at baseline were risk factors for final visual impairment.
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http://dx.doi.org/10.3390/pathogens10040390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063932PMC
March 2021

Protocol: Prospective observational study investigating the prevalence and clinical outcome of portopulmonary hypertension in Japanese patients with chronic liver disease.

PLoS One 2021 1;16(4):e0249435. Epub 2021 Apr 1.

Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.

Background: Portopulmonary hypertension (PoPH) is a subtype of the pulmonary arterial hypertension (PAH) associated with portal hypertension. There is a dissociation between the proportion of PoPH in PAH and that of PoPH in patients with liver cirrhosis, suggesting PoPH underdiagnosis and an incomplete understanding of this entity in the clinical setting. Specifically, real-world data in Japan is largely unknown as compared with in Europe and the United States. The present study aims to elucidate the prevalence and etiology of PoPH in Japanese patients with chronic liver disease.

Methods And Design: In this prospective, single-center, observational investigation of PoPH patients with chronic liver disease, a targeted 2,500 Japanese adult patients regularly visiting Shinshu University Hospital in Matsumoto, Japan, for chronic liver disease will complete a standardized questionnaire on the presence of PoPH symptoms. If the respondent has signs of possible PoPH, ultrasound echocardiography (UCG) will be performed as a primary screening. In the case that UCG findings indicate pulmonary hypertension, the patient will be referred to a cardiologist for further evaluation, whereby a definitive diagnosis PoPH can be made. PoPH prevalence and etiology will be investigated at the time of diagnosis. Afterwards, patients with PoPH will be followed for five years for determination of survival rate.

Discussion: This study will reveal the prevalence, etiology, and 5-year survival rate of PoPH in Japanese patients with chronic liver disease.

Trial Registration: This study is being performed at Shinshu University following registration as UMIN 000042287 on October 29, 2020.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249435PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016266PMC
April 2021

Ten-year changes in visual acuity at baseline and at 2 years after treatment in a Japanese population with age-related macular degeneration.

Graefes Arch Clin Exp Ophthalmol 2020 Nov 17. Epub 2020 Nov 17.

Department of Ophthalmology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan.

Purpose: We investigated 10-year changes in baseline best-corrected visual acuity (BCVA), as well as functional and anatomical changes at 1 and 2 years after initial treatment, in eyes with treatment-naïve neovascular age-related macular degeneration (nAMD).

Methods: This retrospective, multicenter, case series reviewed patients with treatment-naïve nAMD who underwent initial treatment from 2006 to 2015, using photodynamic therapy (PDT), anti-vascular endothelial growth factor (VEGF), or a combination of PDT and anti-VEGF. BCVA and central retinal subfield thickness (CRST), were measured at baseline and at 1 or 2 years of follow-up.

Results: In total, 3096 eyes of 3096 patients were included from 14 hospitals. Mean BCVA at baseline became significantly better over the 10-year study period (P < 0.001). BCVA at 1 year significantly improved from baseline in patients who underwent initial treatment from 2009 to 2015 (P = 0.001, 2009; P = 0.004, 2010; P = 0.01, 2011; P < 0.001, 2012-2015). BCVA at 2 years significantly improved from baseline in patients who underwent initial treatment from 2012 to 2015 (P < 0.001, 2012; P < 0.001, 2013-2015). CRST at 1 year decreased significantly from CRST at baseline, each year from 2006 to 2015 (P < 0.001, 2006-2015). CRST at 2 years decreased significantly from CRST at baseline, each year from 2006 to 2015 (P = 0.03, 2006; P < 0.001, 2007-2015).

Conclusion: Baseline BCVA with treatment-naïve nAMD tended to become better during the study period. BCVA at 1 year improved in the era of anti-VEGF; BCVA at 2 years improved in patients who underwent initial treatment in 2012 or later; and CRST decreased in each year during the study period.
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http://dx.doi.org/10.1007/s00417-020-05005-yDOI Listing
November 2020

Characterization of brown adipose tissue thermogenesis in the naked mole-rat (Heterocephalus glaber), a heterothermic mammal.

Sci Rep 2020 11 10;10(1):19488. Epub 2020 Nov 10.

Department of Aging and Longevity Research, Kumamoto University, Kumamoto, 860-0811, Japan.

The naked mole-rat (NMR) is a heterothermic mammal that forms eusocial colonies consisting of one reproductive female (queen), several reproductive males, and subordinates. Despite their heterothermy, NMRs possess brown adipose tissue (BAT), which generally induces thermogenesis in cold and some non-cold environments. Previous studies suggest that NMR-BAT induces thermogenesis by cold exposure. However, detailed NMR-BAT characteristics and whether NMR-BAT thermogenesis occurs in non-cold environments are unknown. Here, we show beta-3 adrenergic receptor (ADRB3)-dependent thermogenic potential of NMR-BAT, which contributes to thermogenesis in the isolated queen in non-cold environments (30 °C). NMR-BAT expressed several brown adipocyte marker genes and showed noradrenaline-dependent thermogenic activity in vitro and in vivo. Although our ADRB3 inhibition experiments revealed that NMR-BAT thermogenesis slightly delays the decrease in body temperature in a cold environment (20 °C), it was insufficient to prevent the decrease in the body temperatures. Even at 30 °C, NMRs are known to prevent the decrease of and maintain their body temperature by heat-sharing behaviors within the colony. However, isolated NMRs maintained their body temperature at the same level as when they are in the colony. Interestingly, we found that queens, but not subordinates, induce BAT thermogenesis in this condition. Our research provides novel insights into NMR thermoregulation.
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http://dx.doi.org/10.1038/s41598-020-74929-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656259PMC
November 2020

Cardio-renal and cardio-hepatic interactions predict cardiovascular events in elderly patients with heart failure.

PLoS One 2020 23;15(10):e0241003. Epub 2020 Oct 23.

Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.

Background: The composite Model for End-Stage Liver Disease Excluding International Normalized Ratio Score (MELD-XI) is a novel tool to evaluate cardio-renal and cardio-hepatic interactions in patients with advanced heart failure (HF). However, its prognostic ability remains unclear in elderly HF patients.

Methods And Results: From July 2014 to July 2018, patients hospitalized for HF were prospectively recruited at 16 centers. Clinical features, laboratory findings, and echocardiography results were assessed prior to discharge. Cardiovascular (CV) death and HF re-hospitalization were recorded. Of the 676 patients enrolled, 264 (39.1%) experienced CV events throughout a 1-year median follow-up period. Patients with high MELD-XI were predominantly male and had a higher prevalence of NYHA III/IV, history of HF admission, hyperuricemia, ventricular tachycardia, anemia, and ischemic heart disease. In Kaplan-Meyer analysis, patients with higher MELD-XI (≥11) scores showed a worse prognosis than did those with lower (<11) scores (log-rank p≤0.001). Multivariate Cox proportional hazards testing revealed MELD-XI as an independent predictor of CV events (HR: 1.033, 95% CI: 1.006-1.061, p = 0.015) after adjusting for age, gender, body mass index, NYHA III/IV, prior HF hospitalization, systolic blood pressure, ischemic etiology, ventricular tachycardia, anemia, BNP, and left ventricular ejection fraction.

Conclusions: Cardio-renal and cardio-hepatic interactions predicted CV events in aged HF patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241003PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584193PMC
December 2020

UCP1-dependent and UCP1-independent metabolic changes induced by acute cold exposure in brown adipose tissue of mice.

Metabolism 2020 12 14;113:154396. Epub 2020 Oct 14.

Department of Nutrition and Metabolism, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.

Background: Brown adipose tissue (BAT) is a site of metabolic thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1) and represents a target for a therapeutic intervention in obesity. Cold exposure activates UCP1-mediated thermogenesis in BAT and causes drastic changes in glucose, lipid, and amino acid metabolism; however, the relationship between these metabolic changes and UCP1-mediated thermogenesis is not fully understood.

Methods: We conducted metabolomic and GeneChip array analyses of BAT after 4-h exposure to cold temperature (10 °C) in wild-type (WT) and UCP1-KO mice.

Results: Cold exposure largely increased metabolites of the glycolysis pathway and lactic acid levels in WT, but not in UCP1-KO, mice, indicating that aerobic glycolysis is enhanced as a consequence of UCP1-mediated thermogenesis. GeneChip array analysis of BAT revealed that there were 2865 genes upregulated by cold exposure in WT mice, and 838 of these were upregulated and 74 were downregulated in UCP1-KO mice. Pathway analysis revealed the enrichment of genes involved in fatty acid (FA) β oxidation and triglyceride (TG) synthesis in both WT and UCP1-KO mice, suggesting that these metabolic pathways were enhanced by cold exposure independently of UCP1-mediated thermogenesis. FA and cholesterol biosynthesis pathways were enhanced only in UCP1-KO mice. Cold exposure also significantly increased the BAT content of proline, tryptophan, and phenylalanine amino acids in both WT and UCP1-KO mice. In WT mice, cold exposure significantly increased glutamine content and enhanced the expression of genes related to glutamine metabolism. Surprisingly, aspartate was almost completely depleted after cold exposure in UCP1-KO mice. Gene expression analysis suggested that aspartate was actively utilized after cold exposure both in WT and UCP1-KO mice, but it was replenished from intracellular N-acetyl-aspartate in WT mice.

Conclusions: These results revealed that cold exposure induces UCP1-mediated thermogenesis-dependent glucose utilization and UCP1-independent active lipid metabolism in BAT. In addition, cold exposure largely affects amino acid metabolism in BAT, especially UCP1-dependently enhances glutamine utilization. These results contribute a comprehensive understanding of UCP1-mediated thermogenesis-dependent and thermogenesis-independent metabolism in BAT.
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http://dx.doi.org/10.1016/j.metabol.2020.154396DOI Listing
December 2020

Vitreous levels of interleukin-35 as a prognostic factor in B-cell vitreoretinal lymphoma.

Sci Rep 2020 09 24;10(1):15715. Epub 2020 Sep 24.

Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.

Vitreoretinal lymphoma (VRL) is a rare disease of B-cell origin with poor prognosis. Regulatory cytokines promote tumor development by suppressing antitumor immunity in several cancer types, including B-cell malignancies. To identify the regulatory cytokines associated with poor prognosis in patients with B-cell VRL, we determined the regulatory cytokines profiles in the vitreous humor of patients with VRL. This retrospective study included 22 patients with VRL, 24 with non-infectious uveitis (NIU), and 20 with idiopathic epiretinal membrane (control). Vitreous concentrations of regulatory cytokines were assessed using a cytometric beads assay and association with clinical data was examined. IL-35 and soluble IL-2 receptor α levels were significantly higher in patients with VRL and NIU than those in the control group. The 5-year overall survival (OS) rates for the group with high intravitreal IL-35 was significantly poorer than those for the group with low intravitreal IL-35, who were diagnosed with VRL at the onset (P = 0.024, log-rank test). The 5-year OS rates with intravitreal IL-35 levels above and below the median were 40.0% and 83.3%, respectively. Our results suggest that high intravitreal IL-35 levels indicate poor prognosis for patients diagnosed with B-cell VRL at the onset.
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http://dx.doi.org/10.1038/s41598-020-72962-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519124PMC
September 2020

Influence of extended depth of focus intraocular lenses on visual field sensitivity.

PLoS One 2020 14;15(9):e0237728. Epub 2020 Sep 14.

Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan.

Purpose: To investigate the influence of EDOF IOLs, TECNIS Symfony® (Johnson & Johnson Surgical Vision, Inc.), on visual field sensitivity and to compare the IOLs with other kinds of IOLs.

Methods: The subjects included the normal fellow eyes of patients who underwent the Humphrey Field Analyzer (HFA) 30-2 with Swedish Interactive Threshold Algorithm Fast within 6 months after cataract due to glaucoma or suspected glaucoma. Each parameter of HFA was compared among eyes implanted with TENIS Symfony® (EDOF group), diffractive bifocal IOLs (bifocal group), and monofocal IOLs (monofocal group).

Results: The total of 76 eyes, including 24 eyes in the EDOF group, 26 eyes in the bifocal group, and 26 eyes in the monofocal group, were included in this study. Mean deviation (MD) of HFA was -0.24±0.58 dB in the EDOF group, -1.38±0.58 dB in the bifocal group, and 0.02±0.44 dB in the monofocal group. Foveal threshold (FT) of HFA was 35.8±1.6 dB in the EDOF group, 33.6±1.7 dB in the bifocal group, and 36.6±1.4 dB in the monofocal group. In both MD and FT, there was significant difference between the bifocal group and the others (p<0.001). There was no difference between the EDOF group and the monofocal group. Moreover, there was no significant difference between the three groups about pattern standard deviation (PSD) of HFA.

Conclusion: TECNIS Symfony® may have little influence on visual field sensitivity, whereas diffractive bifocal IOLs decrease visual field sensitivity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237728PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489530PMC
October 2020

Safety and efficacy of brilliant blue g250 (BBG) for lens capsular staining: a phase III physician-initiated multicenter clinical trial.

Jpn J Ophthalmol 2020 Sep 18;64(5):455-461. Epub 2020 Aug 18.

Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.

Purpose: To evaluate the safety and efficacy of BBG (Brilliant Blue G250) for lens capsular staining during cataract surgery with continuous curvilinear capsulorhexis.

Study Design: Prospective clinical study.

Methods: This clinical trial enrolled 30 eyes of 30 patients who underwent cataract surgery with BBG (0.25 mg/mL Brilliant Blue G250) for capsular staining. Visualization of the lens capsule and the ease of capsulorhexis with BBG staining were evaluated in five grades (grade 0 to 4) by the Independent Data Monitoring Committee and the surgeons. The safety of BBG was also evaluated in terms of ocular and systemic tolerance for 7 days after surgery.

Results: The use of BBG improved visualization of the lens capsule and complete capsulorhexis was performed in all patients. The major endpoint (Independent Data Monitoring Committee evaluation) showed that use of BBG improved visualization of the lens capsule and the ease of capsulorhexis (grades 2 to 4); the committee's grading results were similar to those of the surgeons. Frequent complications observed in more than two eyes were conjunctival injection, corneal edema and intraocular pressure elevation. No severe complications were observed in ocular and systemic evaluations.

Conclusion: BBG staining contributed to improved visualization of the lens capsule and aided in the completion of capsulorhexis during cataract surgery. The use of BBG for capsular staining also exhibited favorable safety results.
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http://dx.doi.org/10.1007/s10384-020-00763-yDOI Listing
September 2020

A needle-type biofuel cell using enzyme/mediator/carbon nanotube composite fibers for wearable electronics.

Biosens Bioelectron 2020 Oct 12;165:112287. Epub 2020 May 12.

Graduate School of Information, Production and Systems, Waseda University, 2-7 Hibikino, Wakamatsu, Kitakyushu, Fukuoka, 808-0135, Japan. Electronic address:

To realize direct power generation from biofuels in natural organisms, we demonstrate a needle-type biofuel cell (BFC) using enzyme/mediator/carbon nanotube (CNT) composite fibers with the structure Osmium-based polymer/CNT/glucose oxidase/Os-based polymer/CNT. The composite fibers performed a high current density (10 mA/cm) in 5 mM artificial blood glucose. Owing to their hydrophilicity, they also provided sufficient ionic conductivity between the needle-type anode and the gas-diffusion cathode. When the tip of the anodic needle was inserted into natural specimens of grape, kiwifruit, and apple, the assembled BFC generated powers of 55, 44, and 33 μW from glucose, respectively. In addition, the power generated from the blood glucose in mouse heart was 16.3 μW at 0.29 V. The lifetime of the BFC was improved by coating an anti-fouling polymer 2-methacryloyloxyethyl phosphorylcholine (MPC) on the anodic electrode, and sealing the cathodic hydrogel chamber with medical tape to minimize the water evaporation without compromising the oxygen permeability.
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http://dx.doi.org/10.1016/j.bios.2020.112287DOI Listing
October 2020

Role of the Neurokinin-1 Receptor in the Promotion of Corneal Epithelial Wound Healing by the Peptides FGLM-NH2 and SSSR in Neurotrophic Keratopathy.

Invest Ophthalmol Vis Sci 2020 07;61(8):29

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Purpose: Neurotrophic keratopathy is a corneal epitheliopathy induced by trigeminal denervation that can be treated with eyedrops containing the neuropeptide substance P (or the peptide FGLM-NH2 derived therefrom) and insulin-like growth factor 1 (or the peptide SSSR derived therefrom). Here, we examine the mechanism by which substance P (or FGLM-NH2) promotes corneal epithelial wound healing in a mouse model of neurotrophic keratopathy.

Methods: The left eye of mice subjected to trigeminal nerve axotomy in the right eye served as a model of neurotrophic keratopathy. Corneal epithelial wound healing was monitored by fluorescein staining and slit-lamp examination. The distribution of substance P, neurokinin-1 receptor (NK-1R), and phosphorylated Akt was examined by immunohistofluorescence analysis. Cytokine and chemokine concentrations in intraocular fluid were measured with a multiplex assay.

Results: Topical administration of FGLM-NH2 and SSSR promoted corneal epithelial wound healing in the neurotrophic keratopathy model in a manner sensitive to the NK-1R antagonist L-733,060. Expression of substance P and NK-1R in the superficial layer of the corneal epithelium decreased and increased, respectively, in model mice compared with healthy mice. FGLM-NH2 and SSSR treatment suppressed the production of interleukin-1α, macrophage inflammatory protein 1α (MIP-1α) and MIP-1β induced by corneal epithelial injury in the model mice. It also increased the amount of phosphorylated Akt in the corneal epithelium during wound healing in a manner sensitive to prior L-733,060 administration.

Conclusions: The substance P-NK-1R axis promotes corneal epithelial wound healing in a neurotrophic keratopathy model in association with upregulation of Akt signaling and attenuation of changes in the cytokine-chemokine network.
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http://dx.doi.org/10.1167/iovs.61.8.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425742PMC
July 2020

Effect of Lipopolysaccharide and Muramyl Dipeptide on Apoptosis of Bovine Mammary Gland Lymphocytes.

Animals (Basel) 2020 Jun 5;10(6). Epub 2020 Jun 5.

Department of Immunology, Veterinary Research Institute, Hudcova 70, 621 00 Brno, Czech Republic.

The aim of this study was to evaluate whether apoptosis of lymphocytes is modulated by stimulation by lipopolysaccharide (LPS) of or muramyl dipeptide (MDP). Cell populations were obtained by lavaging of the mammary glands 24, 48, 72, and 168 hours following intramammary induced inflammation. The portion of apoptotic lymphocytes peaked at 48 hours after treatment with LPS or MDP. The analysis of CD44 expression of the same cell populations showed a higher percentage of CD44-positive lymphocytes 24- and 48-hours following induction of inflammation by LPS or MDP. The results demonstrate that during both experimental infection of bovine mammary glands with LPS or MDP, apoptosis of lymphocytes was induced in the initial phase of the inflammatory response and CD44 was also overexpressed at the beginning of inflammation. These data suggest a connection of lymphocyte apoptosis with the expression of CD44 receptors.
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http://dx.doi.org/10.3390/ani10060990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341217PMC
June 2020

A Trinity regimen with aflibercept for treatment-naïve neovascular age-related macular degeneration: 2-year outcomes.

Graefes Arch Clin Exp Ophthalmol 2020 Aug 21;258(8):1663-1670. Epub 2020 May 21.

Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube City, Yamaguchi, 755-0046, Japan.

Purpose: To evaluate the advantages of the Trinity regimen for treatment-naïve neovascular age-related macular degeneration (nAMD).

Methods: Thirty-one treatment-naïve nAMD eyes were treated using the Trinity regimen with an intravitreal aflibercept injection (IVA) and evaluated after 24 months. Three treatment methods, pro re nata (PRN), treat and extend (TAE), and fixed regimen were changed depending on recurrence frequency. After the initial treatment, PRN or TAE (started for 4 or 8 weeks) was selected as per the recurrence interval. Subsequently, the recurrence interval became constant, transitioning from a TAE to fixed regimen. When the recurrence frequency became irregular, the treatment regimen was changed to TAE.

Results: After the initial treatment, 15 eyes (48.4%) were allocated to the PRN group, 12 (38.7%) to the TAE 8-week group, and 4 (12.9%) to the TAE 4-week group. Mean logMAR significantly improved in all cases, 0.53 ± 0.40 at baseline to 0.36 ± 0.34 at 24 months (p < 0.01), in the PRN group (0.63 ± 0.46 to 0.42 ± 0.43, p < 0.01), and the TAE 8-week group (0.44 ± 0.29 to 0.27 ± 0.19, p < 0.05). LogMAR in the TAE 4-week group was maintained. The mean number of injections for all and in the PRN, TAE 8-week, and TAE 4-week groups were 9.7, 5.3, 13.1, and 15.8, respectively, with the PRN group being significantly less (p < 0.01).

Conclusion: The Trinity regimen delivered the benefits of the PRN, TAE, and FIXED regimens while minimizing injections during the early treatment phase without visual loss.

Trial Registration: This trial was registered with the University Hospital Medical Information Network (UMIN ID: 000038335).
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http://dx.doi.org/10.1007/s00417-020-04745-1DOI Listing
August 2020

Simultaneous Vitreoretinal Surgery and Penetrating Keratoplasty without a Keratoprosthesis or Endoscopy for Vitreoretinal Disease Associated with Corneal Opacity.

Case Rep Ophthalmol 2020 Jan-Apr;11(1):127-136. Epub 2020 Mar 19.

Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Japan.

We evaluated the visual outcome of combined penetrating keratoplasty (PKP) and 25G pars plana vitrectomy (PPV) performed without a temporary keratoprosthesis or endoscopy in a patient with vitreoretinal disease complicated by severe corneal opacity. The patient was a 68-year-old woman who had severe corneal opacity and silicone oil in her left eye after several previous intraocular surgeries for rhegmatogenous retinal detachment and proliferative vitreoretinopathy. We successfully performed a combined surgery of conventional PKP followed by 25G PPV without the use of a keratoprosthesis. At 6 months after surgery, visual acuity had not improved, and the density of corneal endothelial cells of the donor cornea had declined from 3,205 to 1,969 cells/mm2. However, corneal transparency remained good, and additional surgery for vitreoretinal disease was not necessary. The combined surgical procedure designed to minimize the number of open-sky steps and to limit vitreoretinal complications thus proved to be safe and achieved stable corneal clarity in a patient with vitreoretinal disease and severe corneal opacity.
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http://dx.doi.org/10.1159/000506589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154262PMC
March 2020

Real-world management of treatment-naïve diabetic macular oedema: 2-year visual outcome focusing on the starting year of intervention .

Br J Ophthalmol 2020 12 13;104(12):1755-1761. Epub 2020 Mar 13.

Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

Background/aims: To investigate the yearly change of real-world outcomes for best corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve diabetic macular oedema (DMO).

Methods: Retrospective analysis of aggregated, longitudinal medical records obtained from 27 retina specialised institutions in Japan from Survey of Treatment for DMO database. A total of 2049 treatment-naïve centre involving DMO eyes of which the initial intervention started between 2010 and 2015, and had been followed for 2 years, were eligible. As interventions, antivascular endothelial growth factor (VEGF) agents, local corticosteroids, macular photocoagulation and vitrectomy were defined. In each eye, baseline and final BCVA, the number of each intervention for 2 years was extracted. Each eye was classified by starting year of interventional treatment.

Results: Although baseline BCVA did not change by year, 2-year improvement of BCVA had been increased, and reached to +6.5 letters in the latest term. There is little difference among starting year about proportions of eyes which BCVA gained >15 letters, in contrast to those which lost >15 letters were decreased by year. The proportion of eyes receiving anti-VEGF therapy was dramatically increased, while those receiving the other therapies were gradually decreased. The proportion of eyes which maintained socially good vision of BCVA>20/40 has been increased and reached to 59.0% in the latest term.

Conclusion: For recent years, treatment patterns for DMO have been gradually but certainly changed; as a result, better visual gain, suppression of worsened eyes and better final BCVA have been obtained. Anti-VEGF therapy has become the first-line therapy and its injection frequency has been increasing.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785163PMC
December 2020

Catalog of NIMS creep data sheets.

Sci Technol Adv Mater 2019 27;20(1):1131-1149. Epub 2019 Nov 27.

Research Center for Structural Materials, National Institute for Materials Science, Tsukuba, Ibaraki, Japan.

The background of the NIMS Creep Data Sheet Project, together with the preliminary study and facilities, material selection, and testing method, is summarized. The outcomes from the project are explained, focusing on the long-term creep strength of ferritic and austenitic heat-resistant steels. In some cases, the slope of the stress versus time-to-rupture curve in the long term differed from that in the short term in a manner that was markedly dependent on the type of material. Heat-to-heat variations in creep strength were recognized for ferritic and austenitic steels, even when the chemical compositions of the steels examined were within the range of specifications. The reasons for the heat-to-heat variations were differences in the chemical composition, in the amounts of minor elements, and in the grain size, among others. The existence of inherent creep strength was discovered in the very long term for ferritic heat-resistant steels. The amounts of minor solute elements affect the inherent creep strength, independently of precipitation strengthening or the dislocation structure. An inflection point was observed in the tertiary creep stage for a low-alloy steel and for austenitic stainless steels when precipitation occurred during creep. A region-splitting analysis method was proposed for long-term creep strength evaluation for high-chromium ferritic steels. This method was used to review the allowable stress of high-chromium ferritic steels in Japan. A metallographic atlas, time-temperature-precipitation diagram, and fracture-mode map were proposed for ferritic and austenitic steels on the basis of creep-ruptured specimens.
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http://dx.doi.org/10.1080/14686996.2019.1697616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006710PMC
November 2019

Real-world management of treatment-naïve diabetic macular oedema in Japan: two-year visual outcomes with and without anti-VEGF therapy in the STREAT-DME study.

Br J Ophthalmol 2020 09 29;104(9):1209-1215. Epub 2019 Nov 29.

Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Japan.

Background/aims: To investigate real-world outcomes for best-corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve, centr-involving diabetic macular oedema (DME).

Methods: Retrospective analysis of longitudinal medical records obtained from 27 institutions specialising in retinal diseases in Japan. A total of 2049 eyes with treatment-naïve DME commencing intervention between 2010 and 2015 who were followed for 2 years were eligible. Interventions for DME included anti-vascular endothelial growth factor (VEGF) therapy, local corticosteroid therapy, macular photocoagulation and vitrectomy. Baseline and final BCVA (logMAR) were assessed. Eyes were classified by the treatment pattern, depending on whether anti-VEGF therapy was used, into an anti-VEGF monotherapy group (group A), a combination therapy group (group B) and a group without anti-VEGF therapy (group C).

Results: The mean 2-year improvement of BCVA was -0.04±0.40 and final BCVA of >20/40 was obtained in 46.3% of eyes. Based on the treatment pattern, there were 427 eyes (20.9%) in group A, 807 eyes (39.4%) in group B and 815 eyes (39.8%) in group C. Mean improvement of BCVA was -0.09±0.39, -0.02±0.40 and -0.05±0.39, and the percentage of eyes with final BCVA of >20/40 was 49.4%, 38.9%, and 52.0%, respectively.

Conclusion: Following 2-year real-world management of treatment-naïve DME in Japan, BCVA improved by 2 letters. Eyes treated by anti-VEGF monotherapy showed a better visual prognosis than eyes receiving combination therapy. Despite treatment for DME being selected by specialists in consideration of medical and social factors, a satisfactory visual prognosis was not obtained, but final BCVA remained >20/40 in half of all eyes.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577088PMC
September 2020

Prominin-1 Modulates Rho/ROCK-Mediated Membrane Morphology and Calcium-Dependent Intracellular Chloride Flux.

Sci Rep 2019 11 4;9(1):15911. Epub 2019 Nov 4.

Developmental Biomedical Science, Division of Biological Sciences, Nara Institute of Science and Technology, 8916-5, Takayama-cho, Ikoma, 630-0192, Japan.

Membrane morphology is an important structural determinant as it reflects cellular functions. The pentaspan membrane protein Prominin-1 (Prom1/CD133) is known to be localised to protrusions and plays a pivotal role in migration and the determination of cellular morphology; however, the underlying mechanism of its action have been elusive. Here, we performed molecular characterisation of Prom1, focussing primarily on its effects on cell morphology. Overexpression of Prom1 in RPE-1 cells triggers multiple, long, cholesterol-enriched fibres, independently of actin and microtubule polymerisation. A five amino acid stretch located at the carboxyl cytosolic region is essential for fibre formation. The small GTPase Rho and its downstream Rho-associated coiled-coil-containing protein kinase (ROCK) are also essential for this process, and active Rho colocalises with Prom1 at the site of initialisation of fibre formation. In mouse embryonic fibroblast (MEF) cells we show that Prom1 is required for chloride ion efflux induced by calcium ion uptake, and demonstrate that fibre formation is closely associated with chloride efflux activity. Collectively, these findings suggest that Prom1 affects cell morphology and contributes to chloride conductance.
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http://dx.doi.org/10.1038/s41598-019-52040-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828804PMC
November 2019

REM sleep-active MCH neurons are involved in forgetting hippocampus-dependent memories.

Science 2019 09;365(6459):1308-1313

Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.

The neural mechanisms underlying memory regulation during sleep are not yet fully understood. We found that melanin concentrating hormone-producing neurons (MCH neurons) in the hypothalamus actively contribute to forgetting in rapid eye movement (REM) sleep. Hypothalamic MCH neurons densely innervated the dorsal hippocampus. Activation or inhibition of MCH neurons impaired or improved hippocampus-dependent memory, respectively. Activation of MCH nerve terminals in vitro reduced firing of hippocampal pyramidal neurons by increasing inhibitory inputs. Wake- and REM sleep-active MCH neurons were distinct populations that were randomly distributed in the hypothalamus. REM sleep state-dependent inhibition of MCH neurons impaired hippocampus-dependent memory without affecting sleep architecture or quality. REM sleep-active MCH neurons in the hypothalamus are thus involved in active forgetting in the hippocampus.
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http://dx.doi.org/10.1126/science.aax9238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378274PMC
September 2019

Role of brown adipose tissue in body temperature control during the early postnatal period in Syrian hamsters and mice.

J Vet Med Sci 2019 Oct 6;81(10):1461-1467. Epub 2019 Sep 6.

Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan.

Brown adipose tissue (BAT) contributes to non-shivering thermogenesis and plays an important role in body temperature control. The contribution of BAT thermogenesis to body temperature control in a non-cold environment was evaluated using developing hamsters. Immunostaining for uncoupling protein 1 (UCP1), a mitochondrial protein responsible for BAT thermogenesis, indicated that interscapular fat tissue had matured as BAT at day 14. When pups were placed on a thermal plate kept at 23°C, the body surface temperature decreased in day 7- and 10-day-old pups but was maintained at least for 15 min in 14-day-old pups, indicating that hamsters are unable to maintain their body temperature until around day 14 even in a non-cold environment. Body temperature maintenance was also evaluated in UCP1-deficient mice. BAT analysis showed that the UCP1 protein level in Ucp1 Hetero mice was 61.3 ± 1.4% of that in wild-type (WT) mice and was undetected in Ucp1 knockout (KO) mice. When 12-day-old pups were place on a thermal plate at 23°C, body surface temperature was maintained for at least 15 min in WT and Hetero mice but gradually dropped by 2.4 ± 0.2°C in 15 min in KO mice. It is concluded that BAT thermogenesis is indispensable for body temperature maintenance in pups of hamsters and mice, even in the non-cold circumstances. The early life poikilothermy and the later acquirement of homeothermy in hamsters may be because of the postnatal development of BAT.
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http://dx.doi.org/10.1292/jvms.19-0371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863724PMC
October 2019

Up-regulation of the pentose phosphate pathway and HIF-1α expression during neural progenitor cell induction following glutamate treatment in rat ex vivo retina.

Cell Biol Int 2019 Aug 8. Epub 2019 Aug 8.

Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, 755-8505, Japan.

The metabolic state influences the regulation of neural stem/progenitor cells. The pentose phosphate pathway (PPP), an alternative metabolic pathway that operates parallel to glycolysis, not only provides key intermediates for biosynthetic reactions but also controls the fate of neural stem/progenitor cells. We have previously shown that glutamate application leads to the induction of neural progenitor cells in mature ex vivo rat retina. In this study, we investigated whether regulation of the PPP might be changed following glutamate treatment of the retina. Immunoblot analysis revealed that the amount of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP as well as that of 6-phosphogluconate dehydrogenase (6PGD), another enzyme in this pathway, increased in the glutamate-treated retina. Consistent with the fact that both these enzymes generate reduced nicotinamide adenine dinucleotide phosphate (NADPH), the amount of NAPDH in the treated retina was significantly higher compared with that in the untreated retina. We also found that both DNA synthesis as well as the expression of fatty acid synthase (FASN) increased significantly in the glutamate-treated retina. Furthermore, hypoxia-inducible factor 1-α (HIF-1α), a positive transcriptional regulator of PPP enzymes, was up-regulated at both messenger RNA (mRNA) and protein levels. Finally, we found the interaction of HIF-1α with the M2 isozyme of pyruvate kinase (PKM2), with this interaction having been shown to contribute to a positive feedback loop in the control of glycolysis. Our results thus show that specific metabolic change in the PPP occurs in the process of neural progenitor cell induction in the mature rat retina.
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http://dx.doi.org/10.1002/cbin.11212DOI Listing
August 2019

Inhibitory effect of nintedanib on VEGF secretion in retinal pigment epithelial cells induced by exposure to a necrotic cell lysate.

PLoS One 2019 6;14(8):e0218632. Epub 2019 Aug 6.

Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan.

Necrosis is a form of cell death that results in rupture of the plasma membrane and the release of cellular contents, and it can give rise to sterile inflammation in the retina and other tissues. The secretion of vascular endothelial growth factor (VEGF) by retinal pigment epithelial (RPE) cells contributes to retinal homeostasis as well as to pathological angiogenesis. We have now examined the effect of a necrotic cell lysate prepared from human RPE cells (NLR) on the release of VEGF by healthy RPE cells. We found that NLR markedly increased the release of VEGF from RPE cells and that this effect was attenuated by nintedanib, a multiple receptor tyrosine kinase inhibitor, whereas it was unaffected by inhibitors of NF-κB signaling or of caspase-1. NLR also induced the phosphorylation of extracellular signal-regulated kinase (Erk) and signal transducer and activator of transcription 3 (Stat3) in a manner sensitive to inhibition by nintedanib, although inhibitors of Erk and Stat3 signaling pathways did not affect NLR-induced VEGF secretion. In addition, nintedanib attenuated the development of choroidal neovascularization in mice. Our results have thus shown that a necrotic lysate of RPE cells induced VEGF secretion from healthy RPE cells and that this effect was mediated by receptor tyrosine kinase signaling. They therefore suggest that VEGF secretion by healthy RPE cells is a potential therapeutic target for retinal diseases associated with sterile inflammation and pathological angiogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218632PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684070PMC
March 2020

Dendritic cells mediate the anti-inflammatory action of omega-3 long-chain polyunsaturated fatty acids in experimental autoimmune uveitis.

PLoS One 2019 23;14(7):e0219405. Epub 2019 Jul 23.

Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube City, Yamaguchi, Japan.

We previously showed that dietary omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs) suppress inflammation in mice with experimental autoimmune uveitis (EAU). We have now investigated the role of antigen presenting cells (APCs) in this action of ω-3 LCPUFAs. C57BL/6 mice were fed a diet supplemented with ω-3 or ω-6 LCPUFAs for 2 weeks, after which splenocytes were isolated from the mice and cocultured with CD4+ T cells isolated from mice with EAU induced by injection of a human interphotoreceptor retinoid-binding protein peptide together with complete Freund's adjuvant. The proliferation of and production of interferon-γ and interleukin-17 by T cells from EAU mice in vitro were attenuated in the presence of splenocytes from ω-3 LCPUFA-fed mice as compared with those from mice fed ω-6 LCPUFAs. Splenocyte fractionation by magnetic-activated cell sorting revealed that, among APCs, dendritic cells (DCs) were the target of ω-3 LCPUFAs. Adoptive transfer of DCs from mice fed ω-3 LCPUFAs attenuated disease progression in EAU mice as well as the production of pro-inflammatory cytokines by T cells isolated from these latter animals. The proliferation of T cells from control Balb/c mice was also attenuated in the presence of DCs from ω-3 LCPUFA-fed mice as compared with those from ω-6 LCPUFA-fed mice. Furthermore, T cell proliferation in such a mixed lymphocyte reaction was inhibited by prior exposure of DCs from mice fed an ω-6 LCPUFA diet to ω-3 LCPUFAs in vitro. Our results thus suggest that DCs mediate the anti-inflammatory action of dietary ω-3 LCPUFAs in EAU.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219405PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650034PMC
February 2020

Impact of inpatient cardiac rehabilitation on Barthel Index score and prognosis in patients with acute decompensated heart failure.

Int J Cardiol 2019 10 28;293:125-130. Epub 2019 Jun 28.

Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan.

Background: Although cardiac rehabilitation (CR) can improve exercise capacity and quality of life in patients with chronic heart failure (HF), the long-term prognostic influence of inpatient CR on patients with acute decompensated HF (ADHF) is not well established. We examined the impact of inpatient CR on disability and prognosis in patients with ADHF.

Methods: A total of 171 patients admitted for ADHF underwent CR that included resistance training and aerobic exercise. Patient disability was evaluated using Barthel Index (BI) scores at pre- (BI) and post- (BI) rehabilitation. All-cause mortality was retrospectively recorded after discharge.

Results: In the study cohort (median age: 76 years), 46 patients experienced all-cause mortality during a median of 478 days of follow-up. Impaired BI (i.e., BI < 60) was significantly correlated with older age and lower albumin, hemoglobin, estimated glomerular filtration rate (eGFR), and B-type natriuretic peptide (BNP). In Kaplan-Meier analysis, impaired BI and BI were significantly associated with all-cause mortality. Better outcomes were observed for improved BI (ΔBI > 15) among patients with impaired baseline BI. BI was an independent predictor of all-cause mortality after adjusting for age, sex, eGFR, BNP, hemoglobin, albumin, and left ventricular ejection fraction.

Conclusions: Inpatient CR led to improvements in disabilities among patients with ADHF. Baseline disabilities were associated with a poor prognosis. Greater improvements in BI to inpatient CR were significantly related to better outcomes in patients with impaired baseline BI. CR should be indicated for patients with ADHF.
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http://dx.doi.org/10.1016/j.ijcard.2019.06.071DOI Listing
October 2019

Impaired adrenergic agonist-dependent beige adipocyte induction in obese mice.

J Vet Med Sci 2019 Jun 8;81(6):799-807. Epub 2019 Apr 8.

Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan.

Brown adipocytes, which exist in brown adipose tissue (BAT), are activated by adrenergic stimulation, depending on the activity of uncoupling protein 1 (UCP1). Beige adipocytes emerge from white adipose tissue (WAT) in response to chronic adrenergic stimulation. We investigated obesity-related changes in responses of both types of adipocytes to adrenergic stimulation in mice. Feeding of mice with high-fat diets (HFD: 45%-kcal fat) for 14 weeks resulted in significantly higher body and WAT weight compared to feeding with normal diets (ND: 10%-kcal fat). Injection with β3-adrenergic receptor agonist CL316,243 (CL; 0.1 mg/kg, once a day) for one week elevated the mRNA and protein expression levels of UCP1 in BAT, irrespective of diet. In WAT, CL-induced UCP1 expression in ND mice; however, the responses to CL treatment were attenuated in HFD mice, indicating that CL-induced browning of WAT was impaired in obese mice. Flow cytometric analysis revealed a significant decrease in platelet-derived growth factor receptor (PDGFR) α-expressing beige adipocyte progenitors in WAT of HFD mice compared with those of ND mice. Expression of PDGF-B, a PDGFRα ligand, increased in WAT following CL-injection in ND mice, but not in HFD mice. Treatment of mice with a PDGFR inhibitor significantly decreased CL-dependent UCP1 protein induction in WAT. Our study demonstrates that β3-adrenergic stimulation-dependent beige adipocyte induction in WAT is impaired by obesity in mice, potentially due to obesity-dependent reduction in the number of PDGFRα-expressing progenitors and decreased PDGF-B expression.
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http://dx.doi.org/10.1292/jvms.19-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612507PMC
June 2019

Interleukin-6 plays a crucial role in the development of subretinal fibrosis in a mouse model.

Immunol Med 2018 Mar 5;41(1):23-29. Epub 2018 Apr 5.

a Department of Ophthalmology, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan.

Subretinal fibrosis has been recognized as a feature of an advanced stage of exudative age-related macular degeneration (AMD) that leads to irreversible loss of vision. This study was aimed at elucidating roles of interlukin-6 (IL-6) in the development of subretinal fibrosis. Immunohistochemistry (IHC) was performed with anti-human IL-6 antibody in surgically excised choroidal neovascular tissues from patients with exudative AMD. The area of subretinal fibrosis was measured in a mouse subretinal fibrosis model with injection of control small interfering RNA(siRNA) or IL-6 siRNA, or isotype control antibody or anti-IL-6 receptor antibody after peritoneal exudative cells (PECs) injection into the vitreous cavity. PECs derived from IL-6 or IL-6 mice were placed into the subretinal space of IL-6 mice. IL-6 was expressed in the stroma and retinal pigment epithelial (RPE) layer in the choroidal neovascular tissues. IL-6 knockdown or blocking of the IL-6 receptor suppressed the formation of subretinal fibroblastic scars. The area of subretinal fibrosis induced by PECs derived from IL-6 mice was less than that induced by PECs from IL-6 mice. The results suggested that IL-6, expressed by activated macrophages, is a crucial mediator that promotes subretinal fibrosis. Targeting IL-6 and the corresponding signaling pathway would be an attractive therapeutic approach not only in choroidal neovascularization, but also in subretinal fibrosis.
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http://dx.doi.org/10.1080/09114300.2018.1451609DOI Listing
March 2018