RESUMEN
Lindera umbellata (Lu) essential oil primarily contains linalool and has relaxation properties. We investigated the psychological and antibacterial effects of footbath with Lu essential oil. The participants included 20 women without medical history and received two intervention plans: footbath without any essential oil and footbath using Lu essential oil. Next, questionnaires regarding impressions and mood states were provided for them to answer. In addition, their autonomic nervous system activity was measured, and the aerobic viable of count on the feet was determined. The high-frequency value reflecting the parasympathetic nervous system activity significantly increased after footbath using Lu essential oil. In the questionnaire about the mood states, the subscale scores of tension-anxiety, depression, fatigue, and confusion after intervention were lower than those before intervention regardless of the use of the essential oil. Conversely, the anger-hostility score decreased only in the group using Lu essential oil. Furthermore, the decrease in aerobic viable count after intervention was not significantly different between the two groups. Footbath using Lu essential oil increased the parasympathetic nervous system activity and relieved anger. Taken together, we suggest that footbath using Lu essential oil has a relaxation effect.
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Afecto/efectos de los fármacos , Antibacterianos/farmacología , Lindera/química , Aceites Volátiles/farmacología , Monoterpenos Acíclicos/farmacología , Adulto , Aromaterapia/métodos , Sistema Nervioso Autónomo/efectos de los fármacos , Femenino , Humanos , Adulto JovenRESUMEN
Calcium antagonists are used for coronary spastic angina (CSA) treatment. We previously identified a phospholipase C (PLC) -δ1 gene variant that results in enhanced PLC activity in patients with CSA and developed a CSA animal model by generating vascular smooth muscle cell-specific human variant PLC-δ1 overexpression (PLC-TG) mice. In this study, we investigated the molecular mechanism of CSA using the PLC-TG mice and the inhibitory effect of a calcium antagonist, diltiazem hydrochloride (DL).We treated the PLC-TG and wild-type (WT) mice with oral DL or trichlormethiazide (TM) (control) for 2 weeks. Ergometrine injection-induced coronary spasm was observed on the electrocardiogram in all 5 PLC-TG mice treated with TM, but only in 1 of 5 PLC-TG mice treated with DL. Voltage-dependent calcium channel (Cav1.2) phosphorylation and protein kinase C (PKC) activity were enhanced in the aortas of PLC-TG mice treated with TM. DL treatment significantly inhibited Cav1.2 phosphorylation and PKC activity. Although total Cav1.2 expression was similar between WT and PLC-TG mice treated with TM, DL treatment significantly increased its expression in PLC-TG mice. Furthermore, its expression remained high after DL discontinuation. DL and PKC inhibitor suppressed intracellular calcium response to acetylcholine in cultured rat aortic smooth muscle cells transfected with variant PLC-δ1.These results indicate that enhanced PLC activity causes coronary spasm, presumably via enhanced Cav1.2 phosphorylation and PKC activity, both of which were inhibited by DL. Enhanced total Cav1.2 expression after DL discontinuation and high PKC activity may be an important mechanism underlying the calcium antagonist withdrawal syndrome.
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Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo L/metabolismo , Vasoespasmo Coronario/tratamiento farmacológico , Diltiazem/uso terapéutico , Proteína Quinasa C/metabolismo , Animales , Bloqueadores de los Canales de Calcio/farmacología , Vasoespasmo Coronario/metabolismo , Diltiazem/farmacología , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Masculino , Ratones Transgénicos , Fosforilación/efectos de los fármacosRESUMEN
Rivaroxaban (Riv), a direct factor Xa (FXa) inhibitor, exerts anti-inflammatory effects in addition to anticoagulation. However, its role in cardiovascular remodeling is largely unknown. We tested the hypothesis that Riv attenuates the progression of cardiac hypertrophy and fibrosis induced by continuous activation of the renin-angiotensin system (RAS) in renin-overexpressing hypertensive transgenic (Ren-Tg) mice. We treated 12-week-old male Ren-Tg and wild-type (WT) mice with a diet containing Riv (12 mg/kg/day) or a regular diet for 4 weeks. After this, FXa in plasma significantly increased in Ren-Tg mice compared with WT mice, and Riv inhibited this increase. Left ventricular wall thickness (LVWT) and the area of cardiac fibrosis evaluated by Masson's trichrome staining were greater in Ren-Tg mice than in WT mice, and Riv decreased them. Cardiac expression levels of the protease-activated receptor (PAR)-2, tumor necrosis factor-α, transforming growth factor (TGF)-ß1, and collagen type 3 α1 (COL3A1) genes were all greater in Ren-Tg mice than in WT mice, and Riv attenuated these increases. To investigate the possible involvement of PAR-2, we treated Ren-Tg mice with a continuous subcutaneous infusion of 10 µg/kg/day of the PAR-2 antagonist FSLLRY for 4 weeks. FSLLRY significantly decreased LVWT and cardiac expression of PAR-2, TGF-ß1, and COL3A1. In isolated cardiac fibroblasts (CFs), Riv or FSLLRY pretreatment inhibited the FXa-induced increase in the phosphorylation of extracellular signal-regulated kinases. In addition, Riv or FSLLRY inhibited FXa-stimulated wound closure in CFs. Riv exerts a protective effect against cardiac hypertrophy and fibrosis development induced by continuous activation of the RAS, partly by inhibiting PAR-2.
Asunto(s)
Renina , Rivaroxabán , Animales , Cardiomegalia/patología , Inhibidores del Factor Xa/farmacología , Inhibidores del Factor Xa/uso terapéutico , Fibrosis , Masculino , Ratones , Miocardio/patología , Receptor PAR-2 , Renina/genética , Rivaroxabán/farmacología , Rivaroxabán/uso terapéuticoRESUMEN
BACKGROUND: Prolonged sleep is a higher stroke risk, but post-stroke prolonged sleep facilitates stroke recovery. No study has explored the relationship between pre- and post-stroke prolonged sleep and their involvement in stroke-related quality of life (QOL).This study aimed to clarify the role of pre- and post-stroke prolonged sleep in QOL and sleep quality during hospitalization. METHODS: Fifty-one subacute stroke inpatients were enrolled. QOL was assessed by the Stroke and Aphasia QOL Scale-39-J. Sleep quality and lifestyle values were assessed by original questionnaires. RESULTS: Patients in pre-stroke prolonged sleep > 8 h had a higher incidence of post-stroke poor sleep quality than those belonging to the normal or shorter hours (OR 5.33, 95% CI 1.30-21.84, p = 0.047). In addition, pre-stroke prolonged sleep was associated with lower scores of psychosocial QOL and lifestyle values of "accepting disability; caring about what other people think of what you do". In contrast, post-stroke prolonged sleep was associated with the lower risk of post-stroke poor sleep quality (OR 0.27, 95% CI 0.08-0.86, p = 0.045). Post-stroke high sleep quality had higher (better) scores of physical and energy QOL, and lifestyle values of "caring about what other people think of what you do; having some places to go out after discharge" compared with post-stroke poor sleep quality. Post-stroke prolonged sleep was derived from pre-stroke not prolonged sleep rather than pre-stroke prolonged sleep (p = 0.039, Chi-square test). CONCLUSIONS: Pre-stroke prolonged sleep is associated with a higher incidence of post-stroke poor sleep quality and lower scores of QOL and lifestyle values after stroke.
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Calidad de Vida , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Sueño/fisiología , Accidente Cerebrovascular , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Incidencia , Estilo de Vida , Masculino , Persona de Mediana Edad , Calidad de Vida/psicología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/psicología , Encuestas y CuestionariosRESUMEN
BACKGROUND: A third to half of recurrent stroke occur while on antiplatelet therapy, but no study has explored factors relating to prognosis of recurrent ischemic stroke. This study aimed to clarify the risk factors to determine the clinical outcome of recurrent ischemic stroke. METHODS: A total of 1,333 consecutive acute ischemic stroke patients (first nâ¯=â¯492, recurrent nâ¯=â¯841) were enrolled. We explored factors influencing the modified Rankin Scales (mRS) at discharge that included platelet aggregability, preceding medicines, and well-known risks of biochemical data using Chi-square test or Fisher's exact probability test. RESULTS: As to preceding medicines, the proportion of patients who were functionally independent (mRS 0-2) at discharge was higher in preceding P2Y12 inhibitor that suppressed ADP- and collagen-induced macro-aggregation of platelet and Xa inhibitor or warfarin in cardioembolic stroke, but lower in P2Y12 inhibitor and Xa inhibitor or warfarin in lacunar stroke compared with no medicine. Regardless of LDL-cholesterol and HA1c, the mRS at discharge ≤ 2 was increased in the third tertile of serum albumin and body mass index (BMI) in atherothrombotic stroke; serum albumin and high-density lipoprotein cholesterol (HDL-C) in lacunar stroke; and serum albumin, HDL-C and BMI in cardioembolic stroke. Logistic regression analysis identified the following independent predictors for clinical outcome: serum albumin, HDL-C, BMI, and preceding Xa inhibitor and P2Y12 inhibitor. CONCLUSION: Regardless of well-known risk factors such as diabetes and high LDL-C, preceding treatment for Xa inhibitor or P2Y12 inhibitor, serum albumin, HDL-C, and BMI were associated with prognosis in recurrent ischemic stroke.
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Índice de Masa Corporal , Inhibidores del Factor Xa/uso terapéutico , Accidente Cerebrovascular Isquémico/etiología , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Albúmina Sérica Humana/análisis , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , HDL-Colesterol/sangre , Evaluación de la Discapacidad , Femenino , Estado Funcional , Humanos , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/fisiopatología , Masculino , Persona de Mediana Edad , Limitación de la Movilidad , Pronóstico , Recurrencia , Medición de Riesgo , Factores de RiesgoRESUMEN
Spontaneous platelet aggregation is a trigger for additional development of larger thrombi. Micro-aggregation is observed in 10% of diabetes approximately and blocked by P2Y12 inhibitors, whereas macro-aggregation is associated with overexpression of platelet α2-adrenoreceptors and is not blocked by conventional anti-platelet medicines. We examined the incidence of spontaneous platelet macro-aggregation (SPMA) in acute ischemic stroke and analyzed its clinical characteristics. Out of 665 consecutive acute ischemic strokes, SPMA was found in 10 patients (1.5%, one tenth of micro-aggregation) despite no detection in 588 control subjects. Types of ischemic stroke were 4 atherothrombotic, 4 cardioembolic, and 2 lacunar strokes. Stroke with SPMA exhibited higher (worse) values of modified Rankin Scales (mRS) at discharge (3.00 ± 0.53 vs 1.93 ± 0.07, p = 0.042 by Wilcoxon) compared with stroke without SPMA despite no difference at admission. The proportion of patients who were functionally independent (score 0-2 on the mRS) at discharge was lower in stroke with SPMA compared with stroke without SPMA (p < 0.05 by chi-square test; OR 3.60, 95% CI 1.08-12.03; RR 2.04, 95% CI 1.05-2.86). It was intriguing that severe (high magnitude) SPMA was observed in 4 atherothrombotic stroke. Although anti-platelet therapy underwent, the proportion of atherothrombotic patients who were functionally improved and independent at discharge was lower in the presence of SPMA compared with the absence of SPMA (p < 0.05 by chi-square test). The patients with SPMA were more likely to be older, having major disabilities, being less functionally improved during hospitalization, and being less functionally independent at discharge.
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Plaquetas/patología , Accidente Cerebrovascular Isquémico/patología , Agregación Plaquetaria , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Trombosis/sangre , Trombosis/diagnóstico , Trombosis/patologíaRESUMEN
Assessment of skin condition is necessary for providing advice regarding skin self-care to patients with breast cancer who have undergone radiation therapy. Acute and chronic phases of radiodermatitis were analyzed in patients using objective assessment tools in the present study. A total of 18 women who received radiation therapy for breast cancer were enrolled in the present study and their skin surface temperature (SST), hydration level of the skin surface (HL), melanin intensity (MI) and erythema intensity (EI) were measured prior to radiation therapy and six months thereafter. Furthermore, skin condition was assessed using the Common Terminology Criteria for Adverse Events (CTCAE). EI and MI levels at the irradiated site peaked upon the completion of radiation therapy and declined to baseline at 6 months. In contrast, SST levels were elevated at the irradiated site during radiation therapy (P<0.05) and plateaued after its completion. The same parameters in non-irradiated control sites remained unchanged during the study period. HL reached the minimum in irradiated and non-irradiated sites upon completion of radiation therapy. Although HL returned to baseline in the non-irradiated site 6 months after radiation therapy, it remained low in the irradiated site. No relationship between the CTCAE and EI level was observed. In conclusion, the present study demonstrated that objective assessment tools, including SST and EI levels, were useful for assessing skin condition during radiodermatitis. The combination of the CTCAE and objective assessment tools will enable a more accurate assessment of radiodermatitis.
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BACKGROUND: Blackcurrant anthocyanin (BCA) is expected to repair endothelial dysfunction, but it remains unclear whether beneficial effects are present in young healthy persons. This study examines whether supplements containing blackcurrant anthocyanin improve endothelial function and peripheral temperature in young smokers. METHODS: Young, healthy male nonsmokers (N group: n = 11; mean age 22 ± 2 years) and smokers (S group: n = 13; mean age 21 ± 1 years) were enrolled. A randomized and double-blind trial was designed to compare the effects of no supplement, a supplement containing 50 mg of blackcurrant anthocyanin (supplement A), and a supplement containing 50 mg of blackcurrant anthocyanin plus vitamin E (supplement B) on flow-mediated dilatation (FMD) and skin temperature. RESULTS: Under no supplement, FMD was unchanged during the 2 h period after smoking in the N group, whereas it was decreased during the 2 h period after smoking in the S group. Under the A supplement, FMD was decreased 1 h after smoking and returned to the baseline level 2 h after smoking in the S group. The skin temperature in the area of the foot dorsum was decreased in the S group after smoking compared with that in the N group, who did not smoke, whereas under A and B supplements, it was higher in the S group compared with that in the N group. CONCLUSIONS: BCA could attenuate the smoking-induced acute endothelial dysfunction and improve peripheral temperature in young smokers.
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Antocianinas/administración & dosificación , Células Endoteliales/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ribes/química , Adulto , Antocianinas/química , Método Doble Ciego , Células Endoteliales/patología , Endotelio Vascular/efectos de los fármacos , Humanos , Masculino , Fumadores , Fumar/efectos adversos , Fumar/tratamiento farmacológico , Temperatura , Vasodilatación/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND: Aggregation of platelets is a trigger for additional development of larger thrombi. This study aimed to identify factors that may affect platelet aggregability and their role in clinical outcomes in acute ischemic stroke. METHODS: Consecutive acute ischemic stroke patients (nâ¯=â¯352) who were transferred within 24 hours after its onset were enrolled. Peripheral venous blood was sampled to measure platelet aggregability and other parameters. RESULTS: Mean values of spontaneous small-sized platelet aggregates and collagen- or adenosine diphosphate (ADP)-induced large-sized aggregates were elevated in acute ischemic stroke. In atherothrombotic stroke (nâ¯=â¯178), collagen and ADP-induced large-sized aggregates were positively correlated with HbA1c, respectively. High incidence of the modified Rankin Scales (mRS) 5-6 at discharge was associated with diabetes complication (odds ratio [OR] 8.77, 95% confidence interval [CI] 1.32-57.56). The proportion of patients who were functionally independent (the mRS 0-2) at discharge was lower in the middle tertile of collagen and ADP-induced large-sized aggregates than their low tertile (OR 2.46, 95% CI 1.09-5.58; OR 2.43, 95% CI 1.05-5.59, respectively). Prestroke administration of aspirin recovered the proportion of independence at discharge (OR 0.25, 95% CI 0.06-0.99), and ameliorated incidence of the mRS 5-6. On logistic regression analysis, diabetes, HbA1c, collagen-induced large-sized aggregates, and prestroke administration of aspirin remained independent predictors of clinical outcomes in atherothrombotic stroke. In cardioembolic and lacunar stroke, no relations with clinical outcomes were found. CONCLUSIONS: High plasma level of HbA1c is involved in enhanced platelet aggregability in acute atherothrombotic stroke patients, and prestroke administration of aspirin may be beneficial to clinical outcomes.
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Aspirina/uso terapéutico , Plaquetas/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Diabetes Mellitus/sangre , Hemoglobina Glucada/metabolismo , Inhibidores de Agregación Plaquetaria/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Pruebas de Función Plaquetaria/métodos , Accidente Cerebrovascular/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Aspirina/efectos adversos , Biomarcadores/sangre , Plaquetas/metabolismo , Isquemia Encefálica/sangre , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiología , Comorbilidad , Estudios Transversales , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Evaluación de la Discapacidad , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/efectos adversos , Valor Predictivo de las Pruebas , Recuperación de la Función , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
Background An enhanced renin-angiotensin system causes hypertensive renal damage. Factor Xa not only functions in the coagulation cascade but also activates intracellular signaling through protease-activated receptors ( PAR ). We investigated the effects of rivaroxaban, a factor Xa inhibitor, on hypertensive renal damage in hypertensive mice overexpressing renin (Ren-TG). Methods and Results The 12- to 16-week-old Ren-TG and wild-type mice were orally administered with or without 6 or 12 mg/kg of rivaroxaban for 1 or 4 months. Plasma factor Xa was significantly increased in the Ren-TG compared with the wild-type mice and was reduced by 12 mg/kg of rivaroxaban ( P<0.05). Urinary albumin excretion (UAE) was higher in the nontreated 8-month-old Ren-TG than in the wild-type mice (69.6±29 versus 20.1±8.2 µg/day; P<0.01). Treatment with 12 mg/kg of rivaroxaban for 4 months decreased the UAE to 38.1±13.2 µg/day ( P<0.01). Moreover, rivaroxaban treatment attenuated histologic changes of glomerular hypertrophy, mesangial matrix expansion, effacement of the podocyte foot process, and thickened glomerular basement membrane in the Ren-TG. The renal expression of PAR -2 was increased in the Ren-TG, but was inhibited with rivaroxaban treatment. In vitro study using the human podocytes showed that the expressions of PAR -2 and inflammatory genes and nuclear factor--κB activation were induced by angiotensin II stimulation, but were inhibited by rivaroxaban. PAR -2 knockdown by small interfering RNA also attenuated the PAR -2-related inflammatory gene expressions. Conclusions These findings indicate that rivaroxaban exerts protective effects against angiotensin II-induced renal damage, partly through inhibition of the PAR -2 signaling-mediated inflammatory response.
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Albuminuria/metabolismo , Inhibidores del Factor Xa/farmacología , Hipertensión/metabolismo , Glomérulos Renales/efectos de los fármacos , Receptor PAR-2/efectos de los fármacos , Rivaroxabán/farmacología , Albuminuria/etiología , Angiotensina II/farmacología , Animales , Coagulación Sanguínea/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Membrana Basal Glomerular/efectos de los fármacos , Membrana Basal Glomerular/patología , Mesangio Glomerular/efectos de los fármacos , Mesangio Glomerular/patología , Humanos , Hipertensión/complicaciones , Técnicas In Vitro , Inflamación , Glomérulos Renales/patología , Masculino , Ratones , Ratones Transgénicos , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Podocitos/patología , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/metabolismo , Renina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vasoconstrictores/farmacologíaRESUMEN
BACKGROUND: Adherence to healthy lifestyle factors has been shown to improve outcomes after stroke. This study aimed to identify lifestyle factors about eating habits that may affect the quality of life (QOL) in elderly stroke patients. METHODS: Fifty elderly patients with a first-ever stroke were enrolled. QOL was assessed by the Stroke and Aphasia QOL Scale-39-J. Lifestyle factors about eating habits were collected using questionnaires (Questions 1-17) for the intake of salt, calcium, magnesium, potassium, taurine, fiber, and protein, and the frequency of breakfast. RESULTS: QOL of physical, communication, and psychosocial subdomains was better in the low (healthy) tertile of poststroke eating habits (Questions 1-17) compared with the high tertile of post-troke eating habits (Questions 1-17). This relationship appeared in eating habits except for salt intake but not in eating habits of salt intake and directly measured salt intake. Compared with prestroke eating habits score, poststroke eating habits score was decreased (improved) in 36 patients concerning eating habits of salt intake, but only in 12 patients concerning eating habits except for salt intake (P < .05 by chi-square test). Poststroke eating habits of calcium and magnesium were associated with better psychosocial QOL and better physical or energy QOL, respectively. CONCLUSIONS: Poststroke eating habits of calcium and magnesium were associated with QOL in elderly patients with a first-ever stroke. Since eating habits except for salt intake was poorly improved after stroke, intensive interventions regarding eating habits might be important.
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Dieta Saludable , Conducta Alimentaria , Calidad de Vida , Accidente Cerebrovascular/psicología , Factores de Edad , Anciano , Calcio/administración & dosificación , Estudios Transversales , Femenino , Evaluación Geriátrica/métodos , Humanos , Magnesio/administración & dosificación , Masculino , Persona de Mediana Edad , Estado Nutricional , Valor Nutritivo , Factores Protectores , Ingesta Diaria Recomendada , Factores de Riesgo , Conducta de Reducción del Riesgo , Cloruro de Sodio Dietético/administración & dosificación , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/terapia , Rehabilitación de Accidente Cerebrovascular , Encuestas y CuestionariosRESUMEN
Phospholipase C (PLC)-δ1, activated by p122RhoGTPase-activating protein (GAP)/deleted in liver cancer-1 (p122RhoGAP/DLC-1), contributes to the coronary spastic angina (CSA) pathogenesis. The present study aims to further investigate the p122RhoGAP/DLC-1 protein. We examined molecules assisting this protein and identified a scaffold protein-IQ motif-containing GTPase-activating protein 1 (IQGAP1). IQGAP1-C binds to the steroidogenic acute regulatory-related lipid transfer (START) domain of p122RhoGAP/DLC-1, and PLC-δ1 binds to IQGAP1-N, forming a complex. In fluorescence microscopy, small dots of PLC-δ1 created fine linear arrays like microtubules, and IQGAP1 and p122RhoGAP/DLC-1 were colocated in the cytoplasm with PLC-δ1. Ionomycin induced the raft recruitment of the PLC-δ1, IQGAP1, and p122RhoGAP/DLC-1 complex by translocation to the plasma membrane (PM), indicating the movement of this complex is along microtubules with the motor protein kinesin. Moreover, the IQGAP1 protein was elevated in skin fibroblasts obtained from patients with CSA, and it enhanced the PLC activity and peak intracellular calcium concentration in response to acetylcholine. IQGAP1, a novel stimulating protein, forms a complex with p122RhoGAP/DLC-1 and PLC-δ1 that moves along microtubules and enhances the PLC activity.
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Diet-induced metabolic acidosis is associated with the impairment of bone metabolism and an increased risk of a number of chronic noncommunicable diseases, such as type 2 diabetes mellitus and hypertension. Low serum bicarbonate is associated with high mortality in healthy older individuals. Recently, we demonstrated that both coupling factor 6 (CF6)-overexpressing transgenic (TG) and high salt-fed mice which had sustained intracellular acidosis, due to enhanced proton import through ecto-F1Fo complex and/or reduced proton export through Na+-K+ ATPase inhibition, displayed shortened lifespan and early senescence-associated phenotypes such as signs of hair greying and alopecia, weight loss, and/or reduced organ mass. In this study, we searched causative genes of proton-induced aging in CF6-overexpressing TG and high salt-fed mice. We discovered NM_026333 as a novel anti-aging gene which was downregulated in the heart and kidney in both types of mice. NM_026333 protein consists of 269 amino acids with transmembrane region (90-193aa). Induction of NM_026333 or recombinant protein rescued TG cells and CF6-treated human cells from aging hallmarks of impaired autophagy, genomic instability, and epigenetic alteration. NM_026333 protein directly bound plasma membrane Na+-Ca2+ exchanger 1 (NCX1) to suppress its reverse mode, and cancelled proton-induced epigenetic regression of Atg7 that was caused by H3K4 and H4K20 tri-methylation via suppression of demethylase and H4K5 acetylation via suppression of nuclear HDAC3-HDAC4-emerin system. NM_026333 also attenuated proton-induced impaired formation of autolysosome, an increase in nuclear acetylated LC3 II, and acetylation of Atg7. These effects reappeared by NCX1 inhibitor. Furthermore, NCX1 inhibitor extended lifespan compared with vehicle-treatment in TG mice. This study will shed light on novel aging mechanism and provide implications in a target for anti-aging therapy.
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ATPasas de Translocación de Protón Mitocondriales/metabolismo , Factores de Acoplamiento de la Fosforilación Oxidativa/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Autofagia/genética , Autofagia/fisiología , Membrana Celular/metabolismo , Células Cultivadas , Inmunoprecipitación de Cromatina , Epigenómica , Inestabilidad Genómica/efectos de los fármacos , Inestabilidad Genómica/genética , Células HEK293 , Humanos , Ratones , ATPasas de Translocación de Protón Mitocondriales/genética , Factores de Acoplamiento de la Fosforilación Oxidativa/genética , Protones , Transducción de Señal/efectos de los fármacosRESUMEN
Enhanced renin-angiotensin activity contributes to hypertension, albuminuria, and glomerular hypertrophy. The angiotensin (Ang)-converting enzyme (ACE) 2/Ang (1-7)/Mas axis pathway acts against Ang II type 1 receptor (AT1R) signaling. We investigated whether olmesartan (Olm), an AT1R blocker, inhibits albuminuria independently of blood pressure and elucidated the potential mechanisms.Three- to 4-month-old male mice overexpressing renin in the liver (Ren-TG) were given olmesartan (5 mg/kg/day) or hydralazine (Hyd) (3.5 mg/kg/day) orally for 2 months. Ren-TG mice had higher systolic blood pressure (SBP) than wild-type (WT) mice (158.2 ± 6.3 versus 112.8 ± 8.8 mmHg, n = 3-4, P < 0.01). Ren-TG mice treated with Olm or Hyd for 2 months had lower SBP than untreated Ren-TG mice. Urinary albumin excretion (UAE) was significantly increased in Ren-TG mice compared with WT mice (78.2 ± 31.2 versus 28.6 ± 13.8 µg/day, n = 5-6, P < 0.01). Olm treatment for 2 months reduced UAE, whereas Hyd treatment did not. Olm treatment reversed decreased gene and protein expressions of ACE2 and Mas receptor (Mas 1) in the kidney of Ren-TG mice and inhibited enhanced NADPH oxidase (Nox) 4 expression, whereas Hyd treatment had no influence. Furthermore, increased reactive oxygen species (ROS) in the kidney of Ren-TG mice were decreased by Olm treatment but not by Hyd treatment.Olm treatment inhibits albuminuria and glomerular hypertrophy independently of blood pressure not only through its original AT1R blockade but also partly through the enhancement of the ACE2/Ang (1-7)/Mas axis and suppression of ROS generation.
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Albuminuria/tratamiento farmacológico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Presión Sanguínea , Imidazoles/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Tetrazoles/uso terapéutico , Albuminuria/metabolismo , Albuminuria/fisiopatología , Angiotensina I/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Enzima Convertidora de Angiotensina 2 , Animales , Biomarcadores/metabolismo , Western Blotting , Imidazoles/farmacología , Masculino , Ratones , NADPH Oxidasas/metabolismo , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Renina/metabolismo , Tetrazoles/farmacologíaRESUMEN
Diet-induced metabolic acidosis is associated with the impairment of bone metabolism and an increased risk of a number of chronic noncommunicable diseases, such as type 2 diabetes mellitus and hypertension. The serum bicarbonate level is an independent predictor of chronic kidney disease progression. We investigated whether proton accelerates aging by analyzing both coupling factor 6-overexpressing transgenic (TG) and high salt-fed mice which display sustained intracellular acidosis, due to enhanced proton import through ecto-F1 Fo complex and/or reduced proton export through Na+ -K+ ATPase inhibition. Both types of mice displayed shortened lifespan and early senescence-associated phenotypes such as signs of hair greying and alopecia, weight loss, and/or reduced organ mass. In chronic intracellular acidosis mice, autophagy was impaired by regression of Atg7, an increase in nuclear acetylated LC3 II, and acetylation of Atg7. The increase in histone 3 trimethylation at lysine 4 (H3K4me3) and H4K20me3 and the decrease in H3K9me3 and H3K27me3 were observed in the heart and kidney obtained from both TG and high salt-fed mice. The decrease in lamin A/C, emerin, and heterochromatin protein 1α without changes in barrier-to-autointegration factor and high-mobility group box 1 was confirmed in TG and high salt-fed mice. Suppression of nuclear histone deacetylase 3-emerin system is attributable to epigenetic regression of Atg7 and H4K5 acetylation. These findings will shed light on novel aging and impaired autophagy mechanism, and provide implications in a target for antiaging therapy.
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Envejecimiento/fisiología , Epigénesis Genética , Inestabilidad Genómica , Acidosis/etiología , Animales , Autofagia/fisiología , Proteína 7 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/metabolismo , Presión Sanguínea , Ensamble y Desensamble de Cromatina , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , ATPasas de Translocación de Protón Mitocondriales/genética , Factores de Acoplamiento de la Fosforilación Oxidativa/genética , Protones , Cloruro de Sodio Dietético/farmacologíaRESUMEN
BACKGROUNDS: Spontaneous micro-aggregation of platelets (SMAP) is frequently observed in stroke patients and is a trigger for the additional development of larger thrombi. We tested the hypothesis that SMAP may predict clinical outcome in acute ischemic stroke patients. METHODS AND RESULTS: Consecutive acute ischemic stroke patients (n = 358) who were transferred to our hospital within 24 hours after its onset were enrolled. Peripheral venous blood was sampled to measure various parameters when they arrived. SMAP was correlated with plasma brain natriuretic peptide and diastolic blood pressure positively, and with serum albumin and body weight negatively. Multivariable Cox regression analysis showed that only serum albumin was an independent predictor of the SMAP (P = .0023). The proportion of patients who were functionally independent (score 0-2 on the modified Rankin Scales) at discharge was lower in the third tertile of SMAP (higher level) as compared with the first and the second tertiles in ischemic stroke (odds ratio [OR], 5.76; 95 % confidence interval [CI], 3.31-10.05; P < .0001) and atherothrombotic stroke (P = .02 by chi-square test). The lower proportion of patients achieving independence was found in the first tertile of serum albumin (lower level) as compared with the second and third tertiles in ischemic (OR, 4.60; 95% CI, 2.66-7.95; P < .0001), atherothrombotic, and cardioembolic stroke (P = .004 and P < .0001 by chi-square test). On logistic regression analysis, SMAP and serum albumin remained independent predictors of poor outcome in ischemic stroke. CONCLUSIONS: SMAP within 24 hours after stroke onset is a novel independent predictor of clinical outcome in acute ischemic stroke patients.
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Plaquetas/fisiología , Isquemia Encefálica/sangre , Accidente Cerebrovascular/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Isquemia Encefálica/terapia , Femenino , Hospitalización , Humanos , Modelos Lineales , Masculino , Análisis Multivariante , Pronóstico , Modelos de Riesgos Proporcionales , Albúmina Sérica/metabolismo , Accidente Cerebrovascular/terapia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Coupling factor 6 (CF6) forces a counter-clockwise rotation of plasma membrane F1 Fo complex, resulting in proton import and accelerated aging. Inhibitory factor peptide 1 (IF1) suppresses a unidirectional counter-clockwise rotation of F1 Fo complex without affecting ATP synthesis. We tested the hypothesis that IF1 may attenuate CF6-induced aging signaling in CF6-overexpressing transgenic (TG) cells. In IF1-GFP overexpressing wild type (WT) cells, the diffuse peripheral staining of tubular mitochondria was observed with a dense widely distributed network around the nucleus. In TG cells, however, the only peri-nuclear network of fragmented mitochondria was observed at 24 h, but it was developed to a widely distributed mitochondrial network of tubular mitochondria at 72 h. TG cells displayed aging hallmarks of telomere attrition, epigenetic alterations, defective proteostasis, and genomic instability with a decrease in emerin and lamin and loss of heterochromatin. IF1 induction rescued TG cells from telomere attrition, expression of genomic instability with the increase in emerin and lamin, and that of epigenetic alterations with recovery of heterochromatin. In defective proteostasis, IF1 induction restored a potent peri-nuclear staining of autolysosomes compared with the baseline weak staining. The decrease in Atg7 was restored, whereas the increase in P62 was abolished. We conclude that genetic disruption of proton signals by IF1 induction suppressed CF6-induced expression of aging hallmarks such as telomere attrition, epigenetic alterations, defective proteostasis, and genomic instability. Given the widespread biological actions of CF6, the physiological and pathological actions of IF1 may be complex.
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Envejecimiento , Mitocondrias/metabolismo , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Factores de Acoplamiento de la Fosforilación Oxidativa/metabolismo , Proteínas/metabolismo , Animales , Inestabilidad Genómica , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , ATPasas de Translocación de Protón Mitocondriales/genética , Factores de Acoplamiento de la Fosforilación Oxidativa/genética , Proteínas/genética , Proteína Inhibidora ATPasaRESUMEN
High sodium, high glucose, and obesity are important risk factors for age-related diseases such as cardiovascular disease (CVDs), stroke, and cancer. Coupling factor 6 (CF6) is released from vascular endothelial cells and functions as a circulating peptide that inhibits prostacyclin and nitric oxide generation by intracellular acidosis. High glucose elevates CF6 by activation of protein kinase C and p38 mitogen-activated protein kinase, whereas CF6 causes type 2 diabetes mellitus, resulting in a high glucose vicious cycle. Low glucose increases inhibitory factor peptide 1, an endogenous inhibitor of CF6. High salt intake increases CF6 through nuclear factor κB signaling, whereas CF6 induces salt-sensitive hypertension and salt-induced congestive heart failure. Oral administration of vitamin C cancels salt-induced increase in CF6, and estrogen replacement leads to the delayed onset of CF6-induced salt-sensitive hypertension and the rescue from cardiac systolic dysfunction. Because CF6 contributes to the onset of CVDs, nutritional regulation of CF6 will shed light on the understanding of preventive strategy and mechanisms for CVDs and a target for therapy.
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Células Endoteliales/metabolismo , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Factores de Acoplamiento de la Fosforilación Oxidativa/metabolismo , Administración Oral , Ácido Ascórbico/farmacología , Diabetes Mellitus Tipo 2/diagnóstico , Epoprostenol/antagonistas & inhibidores , Epoprostenol/metabolismo , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/etiología , Humanos , Hipertensión/diagnóstico , FN-kappa B/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Proteína Quinasa C/metabolismo , Transducción de Señal , Cloruro de Sodio Dietético/administración & dosificación , Cloruro de Sodio Dietético/efectos adversos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
We reported that coronary spasm was induced in the transgenic mice with the increased phospholipase C (PLC)-δ1 activity. We investigated the effect of enhanced PLC-δ1 on Ca2+ influx and its underlying mechanisms. We used human embryonic kidney (HEK)-293 and coronary arteries smooth muscle cells (CASMC). Intracellular free Ca2+ concentration ([Ca2+ ]i ; nm) was measured by fura-2, and Ca2+ influx was evaluated by the increase in [Ca2+ ]i after addition of extracellular Ca2+ . Acetylcholine (ACh) was used to induce Ca2+ influx. ACh-induced peak Ca2+ influx was 19 ± 3 in control HEK-293 cells and 71 ± 8 in the cells with PLC-δ1 overexpression (P < 0.05 between two groups). Nifedipine partially suppressed this Ca2+ influx, whereas either 2-APB or knockdown of classical transient receptor potential channel 6 (TRPC6) blocked this Ca2+ influx. In the human CASMC, ACh-induced peak Ca2+ influx was 29 ± 6 in the control and was increased to 45 ± 16 by PLC-δ1 overexpression (P < 0.05). Like HEK-293 cells, pretreatment with nifedipine partially suppressed Ca2+ influx, whereas either 2-APB or knockdown of TRPC6 blocked it. ACh-induced Ca2+ influx was enhanced by PLC-δ1 overexpression, and was blocked partially by nifedipine and completely by 2-APB. TRPC-mediated Ca2+ influx may be related to the enhanced Ca2+ influx in PLC-δ1 overexpression.
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Calcio/metabolismo , Vasoespasmo Coronario/enzimología , Vasos Coronarios/enzimología , Regulación Enzimológica de la Expresión Génica , Fosfolipasa C delta/biosíntesis , Canal Catiónico TRPC6/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Vasoespasmo Coronario/genética , Vasos Coronarios/efectos de los fármacos , Células HEK293 , Humanos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/enzimología , Fosfolipasa C delta/genética , Canal Catiónico TRPC6/antagonistas & inhibidoresRESUMEN
BACKGROUND: Interaction of quality of life (QOL) in physical and psychological health and social environment has not been tested in stroke during a posthospitalization period, and a better understanding of the components of QOL would lead to a more integrated and person-centered approach to health management and outcome optimization. We investigated how QOL emerges from the sequelae of stroke and interacts with each other during the posthospitalization period. METHODS: We performed a cross-sectional study in 53 outpatients of stroke survivors (39 men and 14 women with a mean age of 66 years, 46 infarctions, and 7 hemorrhages). RESULTS: Eight QOL domains of psychological health were scored by interview, and 2 of them ("desire to distend what they can do" or "desire to do rehabilitation") were associated with the improvement of physical health during the posthospitalization period (P < .05 and P = .08, respectively). These patients were characterized by the items like "I need to succeed for health improvement, to go home, to go back to work, and to see grandchildren" as goals to achieve their desire (P < .05). In interaction of QOL in psychological health and social environment, another psychological domain "to gain satisfaction from the experience" was closely related to the presence of hobby or work before stroke attack (P < .05). CONCLUSION: During the posthospitalization period, QOL of psychological health may support that of physical health, being associated with the presence of hobby or work before stroke attack.