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1.
Sci Rep ; 12(1): 15977, 2022 09 25.
Article in English | MEDLINE | ID: mdl-36155621

ABSTRACT

In asymptomatic patients with mitral regurgitation (MR), data of exercise-induced pulmonary hypertension (EIPH) are limited, and feasibility of evaluating EIPH is not high. We aimed to investigate prognostic impact of EIPH and its substitute parameters. Exercise stress echocardiography (ESE) were performed in 123 consecutive patients with moderate to severe degenerative MR. The endpoint was a composite of death, hospitalization for heart failure, and worsening of symptoms. EIPH [tricuspid regurgitation peak gradient (TRPG) at peak workload ≥ 50 mmHg] was shown in 57 patients (46%). TRPG at low workload was independently associated with TRPG at peak workload (ß = 0.67, p < 0.001). Early surgical intervention (within 6 months after ESE) was performed in 65 patients. Of the remaining 58 patients with the watchful waiting strategy, the event free survival was lower in patients with EIPH than in patients without EIPH (48.1 vs. 97.0% at 1-year, p < 0.001). TRPG at low workload ≥ 35.0 mmHg as well as EIPH were associated with poor prognosis in patients with the watchful waiting strategy. In conclusion, the importance of ESE and evaluating EIPH in patients with MR was re-acknowledged. TRPG at peak workload can be predicted by TRPG at low workload, and TRPG at low workload may be useful in real-world clinical settings.


Subject(s)
Hypertension, Pulmonary , Mitral Valve Insufficiency , Tricuspid Valve Insufficiency , Echocardiography, Stress , Humans , Hypertension, Pulmonary/diagnostic imaging , Hypertension, Pulmonary/etiology , Mitral Valve Insufficiency/diagnostic imaging , Prognosis , Workload
2.
Nutrients ; 12(2)2020 Feb 14.
Article in English | MEDLINE | ID: mdl-32075202

ABSTRACT

The accumulation of amyloid ß (Aß) in the brain is a major pathological feature of Alzheimer's disease (AD). In our previous study, we demonstrated that coffee polyphenols (CPP) prevent cognitive dysfunction and Aß deposition in the brain of an APP/PS2 transgenic mouse AD model. The underlying mechanisms, however, remain to be elucidated. Here, we investigated the effects of the chronic administration of 5-caffeoylquinic acid (5-CQA), the most abundant component of CPP, on cognitive dysfunction in APP/PS2 mice to identify the role of CPP in Aß elimination. Relative to the untreated controls, the mice fed a 5-CQA-supplemented diet showed significant improvements in their cognitive function assessed by Y-maze and novel object recognition tests. Histochemical analysis revealed that 5-CQA substantially reduced Aß plaque formation and neuronal loss in the hippocampi. Moreover, 5-CQA upregulated the gene encoding low-density lipoprotein receptor-related protein 1, an Aß efflux receptor, and normalized the perivascular localization of aquaporin 4, which facilitates Aß clearance along the paravascular pathway. These results suggest that 5-CQA reduces Aß deposition in the brain by modulating the Aß clearance pathways and ameliorating cognitive decline and neuronal loss in APP/PS2 mice. Thus, 5-CQA may be effective in preventing cognitive dysfunction in AD.


Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/psychology , Amyloid beta-Peptides/metabolism , Brain/metabolism , Coffee , Cognition/drug effects , Cognitive Dysfunction/prevention & control , Phytotherapy , Polyphenols/administration & dosage , Polyphenols/pharmacology , Quinic Acid/analogs & derivatives , Animals , Disease Models, Animal , Female , LDL-Receptor Related Proteins/genetics , LDL-Receptor Related Proteins/metabolism , Male , Mice, Transgenic , Quinic Acid/administration & dosage , Quinic Acid/pharmacology
3.
Neurosci Res ; 154: 35-44, 2020 May.
Article in English | MEDLINE | ID: mdl-31121203

ABSTRACT

Epidemiological studies have found that habitual coffee consumption may reduce the risk of Alzheimer's disease. Coffee contains numerous phenolic compounds (coffee polyphenols) such as chlorogenic acids. However, evidence demonstrating the contribution of chlorogenic acids to the prevention of cognitive dysfunction induced by Alzheimer's disease is limited. The present study investigated the effect of chlorogenic acids on the prevention of cognitive dysfunction in APP/PS2 transgenic mouse model of Alzheimer's disease. Five-week-old APP/PS2 mice were administered a diet supplemented with coffee polyphenols daily for 5 months. The memory and cognitive function of mice was determined using the novel object recognition test, Morris water maze test, and the step-through passive avoidance test. Immunohistochemical analysis revealed that chronic treatment with coffee polyphenols prevented cognitive dysfunction and significantly reduced the amount of amyloid ß (Aß) plaques in the hippocampus. Furthermore, we determined that 5-caffeoylquinic acid, one of the primary coffee polyphenols, did not inhibit Aß fibrillation; however, degraded Aß fibrils. In conclusion, our results demonstrate that coffee polyphenols prevent cognitive deficits and reduce Aß plaque deposition via disaggregation of Aß in the APP/PS2 mouse.


Subject(s)
Alzheimer Disease/prevention & control , Chlorogenic Acid/pharmacology , Coffee/chemistry , Cognitive Dysfunction/prevention & control , Plaque, Amyloid/prevention & control , Polyphenols/pharmacology , Alzheimer Disease/metabolism , Amyloid/drug effects , Amyloid beta-Peptides/metabolism , Animals , Brain/drug effects , Brain/pathology , Cerebral Cortex/drug effects , Chlorogenic Acid/metabolism , Coffee/metabolism , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Male , Memory , Mice , Mice, Transgenic , Morris Water Maze Test/drug effects , Open Field Test/drug effects , Plaque, Amyloid/metabolism , Polyphenols/metabolism , Quinic Acid/analogs & derivatives , Quinic Acid/chemistry , Spatial Learning/drug effects
4.
Dev Biol ; 445(1): 103-112, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30439356

ABSTRACT

Dead end is a vertebrate-specific RNA-binding protein implicated in germ cell development. We have previously shown that mouse Dead end1 (DND1) is expressed in male embryonic germ cells and directly interacts with NANOS2 to cooperatively promote sexual differentiation of fetal germ cells. In addition, we have also reported that NANOS2 is expressed in self-renewing spermatogonial stem cells and is required for the maintenance of the stem cell state. However, it remains to be determined whether DND1 works with NANOS2 in the spermatogonia. Here, we show that DND1 is expressed in a subpopulation of differentiating spermatogonia and undifferentiated spermatogonia, including NANOS2-positive spermatogonia. Conditional disruption of DND1 depleted both differentiating and undifferentiated spermatogonia; however, the numbers of Asingle and Apaired spermatogonia were preferentially decreased as compared with those of Aaligned spermatogonia. Finally, we found that postnatal DND1 associates with NANOS2 in vivo, independently of RNA, and interacts with some of NANOS2-target mRNAs. These data not only suggest that DND1 is a partner of NANOS2 in undifferentiated spermatogonia as well as in male embryonic germ cells, but also show that DND1 plays an essential role in the survival of differentiating spermatogonia.


Subject(s)
Neoplasm Proteins/metabolism , Spermatogonia/metabolism , Animals , Cell Differentiation , Embryonic Germ Cells/metabolism , Male , Mice , Mice, Transgenic , Neoplasm Proteins/physiology , RNA/metabolism , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/physiology , Reproduction/physiology , Spermatogenesis/genetics , Spermatogonia/cytology , Spermatozoa/metabolism , Stem Cells/cytology , Testis/metabolism
5.
J Pharmacol Sci ; 130(2): 72-7, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26738986

ABSTRACT

Non-selective transient receptor potential vanilloid (TRPV) cation channels are activated by various insults, including exposure to heat, acidity, and the compound capsaicin, resulting in sensations of pain in the skin, visceral organs, and oral cavity. Recently, TRPV1 activation was also demonstrated in response to basic pH elicited by ammonia and intracellular alkalization. Tris-hydroxymethyl aminomethane (THAM) is widely used as an alkalizing agent; however, the effects of THAM on TRPV1 channels have not been defined. In this study, we characterized the effects of THAM-induced TRPV1 channel activation in baby hamster kidney cells expressing human TRPV1 (hTRPV1) and the Ca(2+)-sensitive fluorescent sensor GCaMP2 by real-time confocal microscopy. Notably, both capsaicin (1 µM) and pH 6.5 buffer elicited steep increases in the intracellular Ca(2+) concentration ([Ca(2+)]i), while treatment with THAM (pH 8.5) alone had no effect. However, treatment with THAM (pH 8.5) following capsaicin application elicited a profound, long-lasting increase in [Ca(2+)]i that was completely inhibited by the TRPV1 antagonist capsazepine. Taken together, these results suggest that hTRPV1 pre-activation is required to provoke enhanced, THAM-induced [Ca(2+)]i increases, which could be a mechanism underlying pain induced by basic pH.


Subject(s)
Acrylamides/pharmacology , Calcium/metabolism , Capsaicin/pharmacology , TRPV Cation Channels/metabolism , Animals , Capsaicin/analogs & derivatives , Cells, Cultured , Cricetinae , Hydrogen-Ion Concentration , Pain/genetics , TRPV Cation Channels/antagonists & inhibitors
6.
Neuropeptides ; 58: 93-101, 2016 Aug.
Article in English | MEDLINE | ID: mdl-26775231

ABSTRACT

The growth hormone secretagogue receptor (GHS-R) belongs to Gαq-coupled G protein-coupled receptor (GPCR) that mediates growth hormone release, food intake, appetite, glucose metabolism and body composition. Ghrelin has been identified as an endogenous ligand for GHS-R, and it is the only orexigenic peptide found in the peripheral organs. Olanzapine, an atypical antipsychotic agent that binds to and inhibits the activation of GPCR for several neurotransmitters, has metabolic side effects such as excessive appetite and weight gain. Recently, studies have revealed that the orexigenic mechanism of olanzapine is mediated via GHS-R signaling, although the precise mechanisms have not been clarified. In this study, we investigated the effect of olanzapine on ghrelin-mediated GHS-R signaling by using an electrical impedance-based receptor biosensor assay system (CellKey™). Olanzapine at concentrations of 10(-7) and 10(-6)mol/L enhanced ghrelin-induced (10(-10)-10(-8)mol/L) GHS-R activation. A Ca(2+) imaging assay revealed that olanzapine (10(-7) and 10(-6)mol/L) enhanced ghrelin (10(-7) M)-induced GHS-R activity. In contrast, haloperidol (an antipsychotic agent) failed to enhance this ghrelin-mediated GHS-R activation, as demonstrated by both the CellKey™ and Ca(2+) imaging assays. Together, these results suggest that olanzapine, but not haloperidol, promotes appetite by enhancing ghrelin-mediated GHS-R signaling.


Subject(s)
Antipsychotic Agents/pharmacology , Benzodiazepines/pharmacology , Ghrelin/pharmacology , Receptors, Ghrelin/metabolism , Cell Line , Haloperidol/pharmacology , Humans , In Vitro Techniques , MAP Kinase Signaling System/drug effects , Olanzapine
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