Introduction The morbidity and significant health economic impact associated with the chondral lesion has led to a large number of strategies for therapeutic neochondrogenesis. The challenge has been ...to develop techniques that are cost effective single-stage procedures with minimal surgical trauma that have undergone rigorous preclinical scrutiny and robust reproducible assessment of effectiveness. A biological repair requires the generation of a cellular and matrix composite with appropriate signalling for chondrogenic differentiation. Methods and results A technique was developed that allowed chondrogenic primary (uncultured) cells from bone marrow aspirate concentrate, combined with a composite hydrophilic and fibrillar matrix to be applied arthroscopically to a site of a chondral lesion. The construct was tested in vitro and in animal experiments before clinical trials. Clinical trials involved 60 patients in a prospective study. Symptomatic International Cartilage Repair Society grade 3 and 4a lesions were mapped and treated. Pre- and postoperative clinical assessments showed statistically significant improved outcomes; Lysholm Knee Scoring Scale (mean 52.8 to > 76.4; P < 0.05) International Knee Documentation Committee (mean 39 to > 79 P < 0.05) and Knee injury and Osteoarthritis Outcome Score (64.5 to >89.2 P < 0.05). Postoperative magnetic resonance imaging was evaluated morphologically (magnetic resonance observation of cartilage repair tissue, average MOCART score 72) and qualitatively; the regenerate was comparable to native cartilage. Conclusions This technique is effective, affordable, requires no complex tools and delivers a single-stage treatment that is potentially accessible to any centre capable of performing arthroscopic surgery. Good clinical results were found to be sustained at five years of follow-up with a regenerate that appears hyaline like using multiple magnetic resonance measures.
The zafirlukast has been reported to be anti‐inflammatory and widely used to alleviate the symptoms of asthma. However, its influence on insulin secretion in pancreatic β‐cells has not been ...investigated. Herein, we examined the effects of zafirlukast on insulin secretion and the potential underlying mechanisms. Among the cysteinyl leukotriene receptor 1 antagonists, zafirlukast, pranlukast, and montelukast, only zafirlukast enhanced insulin secretion in a concentration‐dependent manner in both low and high glucose conditions and elevated the level of Ca2+i, further activating Ca2+/calmodulin‐dependent protein kinase II (CaMKII), protein kinase B (AKT), and extracellular signal‐regulated kinase (ERK) signaling. These effects were nearly abolished by the L‐type Ca2+ channel antagonist nifedipine, while treatment with thapsigargin, a sarco/endoplasmic reticulum Ca2+ ATPase inhibitor, did not have the same effect, suggesting that zafirlukast primarily induces the entry of extracellular Ca2+ rather than intracellular Ca2+ from the endoplasmic reticulum. Zafirlukast treatment resulting in a significant drop in glucose levels and increased insulin secretion in C57BL/6J mice. These findings will contribute to an improved understanding of the side effects of zafirlukast and potential candidate for a therapeutic intervention in diabetes.
We described a novel function of zafirlukast in pancreatic β‐cells as potent insulin secretagogue. These findings provide comprehensive understanding of zafirlukast drug and show possibility of usage as anti‐diabetic medications.
ABSTRACT
PLC‐β exerts biologic influences through GPCR. GPCRs are involved in regulating glucose‐stimulated insulin secretion (GSIS). Previous studies have suggested that PLC‐βs might play an ...important role in pancreatic β cells. However, because of a lack of the specific inhibitors of PLC‐β isozymes and appropriate genetic models, the in vivo function of specific PLC‐β isozymes in pancreatic β cells and their physiologic relevance in the regulation of insulin secretion have not been studied so far. The present study showed that PLC‐β1 was crucial for β‐cell function by generation of each PLC‐β conditional knockout mouse. Mice lacking PLC‐β1 in β cells exhibited a marked defect in GSIS, leading to glucose intolerance. In ex vivo studies, the secreted insulin level and Ca2+ response in Plcb1f/f; pancreas/duodenum homeobox protein 1 (Pdx1)‐Cre recombinase‐estrogen receptor T2 (CreERt2) islets was lower than those in the Plcb1f/f islets under the high‐glucose condition. PLC‐β1 led to potentiate insulin secretion via stimulation of particular Gq‐protein–coupled receptors. Plcb1f/f; Pdx1‐CreERt2 mice fed a high‐fat diet developed more severe glucose intolerance because of a defect in insulin secretion. The present study identified PLC‐β1 as an important molecule that regulates β cell insulin secretion and can be considered a candidate for therapeutic intervention in diabetes mellitus.—Hwang, H.‐J., Yang, Y. R., Kim, H. Y., Choi, Y., Park, K.‐S., Lee, H., Ma, J. S., Yamamoto, M., Kim, J., Chae, Y. C., Choi, J. H., Coceo, L., Berggren, P.‐O., Jang, H.‐J., Suh, P.‐G. Phospholipase Cβ1 potentiates glucose‐stimulated insulin secretion. FASEB J. 33, 10668–10679 (2019). www.fasebj.org
Rice (Oryza sativa), a monocotyledonous plant that does not cold acclimate, has evolved differently from Arabidopsis (Arabidopsis thaliana), which cold acclimates. To understand the stress response ...of rice in comparison with that of Arabidopsis, we developed transgenic rice plants that constitutively expressed CBF3/DREB1A (CBF3) and ABF3, Arabidopsis genes that function in abscisic acid-independent and abscisic acid-dependent stress-response pathways, respectively. CBF3 in transgenic rice elevated tolerance to drought and high salinity, and produced relatively low levels of tolerance to low-temperature exposure. These data were in direct contrast to CBF3 in Arabidopsis, which is known to function primarily to enhance freezing tolerance. ABF3 in transgenic rice increased tolerance to drought stress alone. By using the 60 K Rice Whole Genome Microarray and RNA gel-blot analyses, we identified 12 and 7 target genes that were activated in transgenic rice plants by CBF3 and ABF3, respectively, which appear to render the corresponding plants acclimated for stress conditions. The target genes together with 13 and 27 additional genes are induced further upon exposure to drought stress, consequently making the transgenic plants more tolerant to stress conditions. Interestingly, our transgenic plants exhibited neither growth inhibition nor visible phenotypic alterations despite constitutive expression of the CBF3 or ABF3, unlike the results previously obtained from Arabidopsis where transgenic plants were stunted.
Activation of nicotinic acetylcholine receptor alpha7 subunit (α7nAChR) by nicotine leads to the improved survival rate in experimental model of sepsis. Previously, we demonstrated that heme ...oxygenase (HO)-1 inducers or carbon monoxide significantly increased survival of lipopolysaccharide (LPS)-induced and cecal ligation and puncture-induced septic mice by reduction of high mobility group box 1 release, a late mediator of sepsis. However, that activation of α7nAChR by nicotine provides anti-inflammatory action through HO-1 upregulation has not been elucidated. Here we show that HO-1-inducible effect by nicotine was mediated through sequential event-Ca(2+) influx, classical protein kinase C activation, and reactive oxygen species production-which activates phosphoinositol-3-kinase/Akt/Nrf-2 pathway. In addition, HO-1 is required for nicotine-mediated suppression of tumor necrosis factor-α, inducible nitric oxide synthase, and high mobility group box 1 expression induced by LPS in macrophages, as evidenced by the fact that nicotine failed to inhibit production of these mediators when HO-1 was suppressed. Importantly, nicotine-induced survival rate was reduced by inhibition of HO-1 in LPS- and cecal ligation and puncture-treated septic mice. Collectively, these data suggest that activation of α7nAChR by nicotine is critical in the regulation of anti-inflammatory process, which could be mediated through HO-1 expression. Thus, we conclude that activation of α7nAChR by nicotine provides anti-inflammatory action through HO-1 upregulation.
N-Substituted glycine peptoid oligomers were used as substrates for azide-alkyne 3 + 2 cycloaddition conjugation reactions and then elaborated through additional rounds of oligomerization and ...cycloaddition. This novel sequential conjugation technique allowed for the generation of complex peptidomimetic products in which multiple heterogeneous pendant groups were site-specifically positioned along the oligomer scaffold. Studies of a water-soluble estradiol-ferrocene peptoid conjugate demonstrated a potential application for the modular synthesis of biosensors.
Purpose Ocular components are traditionally measured using A‐scan ultrasound. With ultrasound, the probe makes contact with the cornea, so there is some problem in children. The IOLMaster is ...non‐contact device that can measure ocular components, so it can be used in children with poor cooperation. We evaluated change of ocular components after cycloplegia in children using the IOLMaster.
Methods One hundred and sixty eight children aged from 3 to 15 years were recruited from the Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine. Children with ocular problem except refractive error were excluded. Pre‐ and post‐cycloplegic corneal curvature (CC), anterior chamber depth (ACD) and axial length (AL) on the right eye were measured with the IOLMaster. We evaluated the change of ocular components after cycloplegia by age and refractive error.
Results ACD was 0.134 ± 0.134mm deeper after cycloplegia (p=.000). The amount of change had statistically significant negative correlation with age (Pearson correlation ‐0.332, p=.006), but it was not significantly different between myopic and hyperopic group after age correction (p=.398). AL was also significantly elongated after cycloplegia (p=.000), but the amount of change was very small (0.011 ± 0.022mm). There was no change in CC after cycloplegia (p=.428).
Conclusion Effect of cycloplegia on ACD in children measured with the IOLMaster was significant. We suppose that the negative correlation between the change of ACD and age may be associated with decreasing accommodation with age.
We describe an efficient protocol to effect multisite conjugation reactions to oligomers on solid-phase support. Sequence-specific N-substituted glycine “oligopeptoids” were utilized as substrates ...for azide−alkyne cycloaddition reactions. Diverse groups, including nucleobases and fluorophores, were conjugated at up to six positions on peptoid side chains with yields ranging from 88 to 96%. This strategy will be broadly applicable for generating polyvalent displays on peptides and other scaffolds, allowing precise control of spacing between the displayed groups.
The structure and composition of passive film formed on Ni in pH 8.5 buffer solution were examined by comparing the photocurrent and Mott–Schottky responses for both the passive film and the ...thermally grown oxide on Ni in air at 400
°C.
The photocurrent spectra for the passive film on Ni are resolved into two spectral components, each of which originated from inner NiO and outer Ni(OH)
2 layers, respectively. The band gap energy (
E
g) for the inner NiO and the outer Ni(OH)
2 were measured to be 4.80
±
0.1 and 3.05
±
0.1
eV, respectively.
E
g (4.80
±
0.1
eV) of the inner NiO of the passive film on Ni was close to that (4.97
eV) of the thermally grown oxide of Ni within an error range, suggesting that the inner NiO in the passive film is crystalline. The Mott–Schottky plots for both the passive film and the thermal oxide film on Ni demonstrated that the two films exhibited p-type semiconductivity with different values of flat band potential (
U
fb); 0.3
V
SCE for the passive film and 0
V
SCE for the thermally grown NiO. An electronic energy band model of P–p heterojunction composed of inner NiO and outer Ni(OH)
2 layers was proposed to explain the photocurrent and Mott–Schottky responses for the passive film on Ni.
Context: Previous studies with small numbers of subjects showed a negative correlation between plasma peptide YY (PYY) levels and obesity. If correct, this would imply that low PYY levels might be ...involved in the pathogenesis of obesity.
Objective: Our objective was to investigate whether plasma PYY levels were correlated with sex and body mass index (BMI).
Design, Setting, and Patients: We conducted a cross-sectional study of 151 normal volunteers (19–90 yr of age) in the Baltimore Longitudinal Study of Aging.
Interventions: All subjects had an oral glucose tolerance test (75 g) performed.
Main Outcome Measures: Immunostaining of human duodenum, BMI, hemoglobin A1c, plasma glucose, insulin, PYY, glucagon like peptide-1 (GLP-1), ghrelin, and leptin were the main outcome measures.
Results: PYY and GLP-1 colocalized in the same cells in human duodenum. Both hormones reached peak plasma levels by 20 min and had similar secretory patterns. The incremental increases in PYY and GLP-1 during that first 20 min were significantly correlated (r2 = 0.388; P < 0.0001). The areas under the curve from 0–120 min for PYY and GLP-1 were similar in both obese and lean participants. Female participants across the range of BMI had significantly higher PYY area under the curve (17,464 ± 1,240 vs. 14,120 ± 806 pmol/liter·min, female vs. male; P < 0.05) compared with male participants.
Conclusions: Our findings show that PYY and GLP-1 are colocalized and cosecreted from L cells and that total secretion of PYY is higher in females than in males, but fasting PYY levels and PYY secretion in response to oral glucose were not in any way correlated with BMI.
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