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The large Ser/Thr protein kinase mTOR signals through two physically distinct multipro- tein complexes called mTOR complexes 1 and 2(mTORC1 and mTORC2). The mTORC1 pathway integrates inputs from nutrients and growth factors for protein synthesis, autophagy, cell growth and proliferation. Dietary restriction delays ageing and extends life span in diverse species including yeast, worm, fly, and mammals such as mouse and monkey. Because in- cidences of many diseases such as cancer, cardiovascular disease, metabolic disease and dementia rise rapidly with age, interventions that delay ageing would greatly benefit health. It has become apparent in recent years that the nutrient sensing mTOR pathways are well con- served among such various species and important regulators of ageing and longevity.
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Envejecimiento , Serina-Treonina Quinasas TOR , Envejecimiento/fisiología , Animales , Autofagia/fisiología , Proliferación Celular , Humanos , Longevidad , Diana Mecanicista del Complejo 1 de la Rapamicina/fisiología , Diana Mecanicista del Complejo 2 de la Rapamicina/fisiología , Ratones , Neoplasias/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/fisiologíaRESUMEN
High plantar flexor moment and limited ankle mobility are known to cause high plantar pressure under the forefoot. Stretching is an effective physical therapy for the limited ankle range of motion (ROM), and electrical stimulation is used to regulate the activity of antagonistic muscle via the action of reciprocal inhibition. Additionally, stretching paired with electrical stimulation has been reported to improve the limited ROM significantly. This study aims to investigate the influences of stretching on triceps surae (STR), electrical stimulation to tibialis anterior (ES), and the combination (ES+STR) on the ROM, kinematic parameters, and plantar pressure distribution during gait in patients with diabetes mellitus. Planter pressure and other parameters were measured before and after the intervention of ES, STR, ES+STR, or the rest sitting on the bed (CON) for 10â min. Pressure time integral under the medial forefoot decreased in the ES+STR compared to CON (P< .05). Interestingly, ES+STR increased passive and dynamic ROM on ankle dorsiflexion during gait and increased the lateral center of pressure excursion (P < .05). Furthermore, these changes were followed by decreased contact duration under the medial forefoot (P < .05). The combined therapy improves ankle mobility during gait and reduces the contact duration and the plantar pressure under the medial forefoot in patients with diabetes mellitus.
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Cardiac mammalian target of rapamycin (mTOR) is necessary and sufficient to prevent cardiac dysfunction in pathological hypertrophy. However, the role of cardiac mTOR in heart failure after ischemic injury remains undefined. To address this question, we used transgenic (Tg) mice with cardiac-specific overexpression of mTOR (mTOR-Tg mice) to study ischemia-reperfusion (I/R) injury in two animal models: 1) in vivo I/R injury with transient coronary artery ligation and 2) ex vivo I/R injury in Langendorff-perfused hearts with transient global ischemia. At 28 days after I/R, mortality was lower in mTOR-Tg mice than littermate control mice [wild-type (WT) mice]. Echocardiography and MRI demonstrated that global cardiac function in mTOR-Tg mice was preserved, whereas WT mice exhibited significant cardiac dysfunction. Masson's trichrome staining showed that 28 days after I/R, the area of interstitial fibrosis was smaller in mTOR-Tg mice compared with WT mice, suggesting that adverse left ventricular remodeling is inhibited in mTOR-Tg mice. In the ex vivo I/R model, mTOR-Tg hearts demonstrated improved functional recovery compared with WT hearts. Perfusion with Evans blue after ex vivo I/R yielded less staining in mTOR-Tg hearts than WT hearts, indicating that mTOR overexpression inhibited necrosis during I/R injury. Expression of proinflammatory cytokines, including IL-6 and TNF-α, in mTOR-Tg hearts was lower than in WT hearts. Consistent with this, IL-6 in the effluent post-I/R injury was lower in mTOR-Tg hearts than in WT hearts. These findings suggest that cardiac mTOR overexpression in the heart is sufficient to provide substantial cardioprotection against I/R injury and suppress the inflammatory response.
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Daño por Reperfusión Miocárdica/prevención & control , Serina-Treonina Quinasas TOR/fisiología , Animales , Autofagia , Western Blotting , Vasos Coronarios/fisiología , ADN/genética , ADN/aislamiento & purificación , Fibrosis , Técnicas In Vitro , Inflamación/genética , Inflamación/patología , Ligadura , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Transgénicos , Isquemia Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/diagnóstico por imagen , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , Miocitos Cardíacos/patología , Necrosis , Perfusión , Reacción en Cadena en Tiempo Real de la Polimerasa , Serina-Treonina Quinasas TOR/genética , UltrasonografíaRESUMEN
OBJECTIVE: To test the hypothesis that intraplaque hemorrhage is a predictor of restenosis after carotid artery stenting (CAS), the association between intraplaque high-intensity signal (HIS) on time-of-flight MR angiography (TOF-MRA), as a marker of intraplaque hemorrhage, and restenosis after CAS was assessed in the present observational study. METHODS: Consecutive patients who underwent initial CAS for atherosclerotic stenosis in the cervical internal carotid artery in the authors' department were enrolled. Of these, patients without preprocedural cervical TOF-MRA were excluded. Outcome measures were ≥ 50% restenosis, defined as a peak systolic velocity of > 1.3 m/sec; or occlusion and ≥ 70% restenosis, defined as a peak systolic velocity of > 2.1 m/sec; or occlusion on carotid duplex ultrasound. RESULTS: Of 230 consecutive patients who underwent initial CAS, 22 without preprocedural cervical TOF-MRA were excluded. Of the remaining 208 patients (mean age 73 years; 33 women), 46 had intraplaque HIS. Ultrasound follow-up was not performed in 4 patients. The median follow-up duration was 3.2 years (interquartile range 1.7-5.1 years). During the follow-up period, 102 patients had ≥ 50% restenosis and 36 had ≥ 70% restenosis. Intraplaque HIS was significantly associated with increased risk of ≥ 50% restenosis (adjusted hazard ratio 2.18; 95% CI 1.28-3.68) and ≥ 70% restenosis (adjusted hazard ratio 3.12; 95% CI 1.32-7.52). CONCLUSIONS: Intraplaque HIS on TOF-MRA was associated with increased risk of restenosis after CAS. The present results indicate that intraplaque hemorrhage is a predictor of restenosis after CAS.
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Estenosis Carotídea , Angiografía por Resonancia Magnética , Anciano , Arterias Carótidas , Arteria Carótida Interna , Estenosis Carotídea/complicaciones , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/cirugía , Constricción Patológica , Femenino , Humanos , Angiografía por Resonancia Magnética/métodos , StentsRESUMEN
BACKGROUND: Fluid-attenuated inversion recovery vascular hyperintensity (FVH) outside of the diffusion-weighted imaging (DWI) lesion, termed FVH-DWI mismatch, may represent penumbral tissue with good collateral status. METHODS: Consecutive patients who underwent endovascular reperfusion therapy (EVT) for acute internal carotid artery (ICA) or middle cerebral artery (MCA)-M1 occlusion were enrolled. FVH-DWI mismatch score was defined as the number of cortical Alberta Stroke Program Early CT Score areas (I and M1 to M6) that involved FVH but no DWI lesion (0 to 7 points). The outcome measure was set as good functional outcome, defined as a modified Rankin Scale score of 0 to 2, at 90 days after onset. RESULTS: Of 196 consecutive patients who underwent EVT for acute ICA or MCA-M1 occlusion, 32 without brain MRI before EVT were excluded, and the remaining 164 were analyzed. The median FVH-DWI mismatch score was 2 (interquartile range, 0 to 4). At 90 days after EVT, 2 patients were lost-to follow-up, and 73 had good functional outcome. The frequency of good functional outcome at 90 days after EVT increased significantly with increasing FVH-DWI mismatch score (P for trend <0.001). FVH-DWI mismatch score was independently associated with good functional outcome at 90 days after onset (adjusted odds ratio per 1 point,1.46; 95% confidence interval, 1.15-1.89). CONCLUSIONS: Patients with large FVH-DWI mismatch had good functional outcome after EVT for acute ICA or MCA-M1 occlusion.
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Endovascular embolization of the middle meningeal artery (MMA) has been reported as an effective method for treating chronic subdural hematoma (CSDH); however, its preventive effect on CSDH following craniotomy is unknown. We present a case in which MMA embolization was ineffective in preventing CSDH following craniotomy. A 56-year-old man who complained of diplopia was diagnosed with sphenoid ridge meningioma with a 3-cm diameter. MMA embolization prior to the operation and total surgical removal of the tumor were performed. Two months postoperatively, the patient complained of headache and hemiparesis of the left side. CSDH with a 15-mm thickness and a midline shift was observed. MMA embolization before inflammation may not play a role in preventing CSDH development because MMA embolization is considered effective in CSDH because it is associated with the blood supply of neovessels that are newly formed due to inflammation. Therefore, MMA embolization might not be effective in preventing the occurrence of CSDH following craniotomy.
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An 82-year-old man was transferred to our hospital due to impaired consciousness. His albumin-corrected calcium level was 14.2 mg/dL, intact parathyroid hormone (PTH) and PTH-related protein levels were reduced, and his 1,25-dihydroxyvitamin D [1,25 (OH) 2VitD] level was elevated at 71.5 pg/mL. Computed tomography revealed masses on the bilateral ribs. The mass on the rib was biopsied and diagnosed as diffuse large B-cell lymphoma (DLBCL). Immunostaining of the biopsy sample with the anti-CYP27B1 antibody revealed the ectopic expression of 1α-hydroxylase in the lesion. We herein report a rare case of hypercalcemia induced by the overproduction of 1,25 (OH) 2VitD in DLBCL ectopically expressing 1α-hydroxylase.
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Hipercalcemia , Linfoma de Células B Grandes Difuso , Anciano de 80 o más Años , Calcifediol/efectos adversos , Calcifediol/metabolismo , Expresión Génica Ectópica , Humanos , Hipercalcemia/inducido químicamente , Linfoma de Células B Grandes Difuso/complicaciones , Masculino , Hormona Paratiroidea/metabolismo , Vitamina D/efectos adversosRESUMEN
BACKGROUND: The efficacy of combined stent retriever (SR) and aspiration catheter (AC; combined technique: CBT) use for acute ischemic stroke (AIS) is unclear. We investigated the safety and efficacy of single-unit CBT (SCBT)-retrieving the thrombus as a single unit with SR and AC into the guide catheter-compared with single use of either SR or contact aspiration (CA). METHODS: We analysed 763 consecutive patients who underwent mechanical thrombectomy for AIS between January 2013 and January 2020, at six comprehensive stroke centers. Patients were divided into SCBT and single device (SR/CA) groups. The successful recanalization with first pass (SRFP) and other procedural outcomes were compared between groups. RESULTS: Overall, 240 SCBT and 301 SR/CA (SR 128, CA 173) patients were analyzed. SRFP (modified Thrombolysis In Cerebral Infarction (mTICI) ≥2c, 43.3% vs 27.9%, p<0.001; mTICI 3, 35.8% vs 25.5%, p=0.009) and final mTICI ≥2b recanalization (89.1% vs 82.0%, p=0.020) rates were significantly higher, puncture-to-reperfusion time was shorter (median (IQR) 43 (31.5-69) vs 55 (38-82.2) min, p<0.001), and the number of passes were fewer (mean±SD 1.72±0.92 vs 1.99±1.01, p<0.001) in the SCBT group. Procedural complications were similar between the groups. In subgroup analysis, SCBT was more effective in women, cardioembolic stroke patients, and internal carotid artery and M2 occlusions. CONCLUSIONS: SCBT increases the SRFP rate and shortens the puncture-to-reperfusion time without increasing procedural complications.
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Isquemia Encefálica , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Isquemia Encefálica/complicaciones , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/cirugía , Catéteres/efectos adversos , Infarto Cerebral/complicaciones , Femenino , Humanos , Estudios Retrospectivos , Stents/efectos adversos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/cirugía , Trombectomía/efectos adversos , Resultado del TratamientoRESUMEN
The protein Ras homolog enriched in brain (Rheb) is a Ras-like small GTPase that activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes cell growth. We previously generated transgenic C57BL/6 mice overexpressing Rheb in ß-cells (B6(Rheb)), which exhibited increased ß-cell size and improved glucose tolerance with higher insulin secretion than wild type C57BL/6 mice. The mice also showed resistance to obesity-induced hyperglycemia, a model of type 2 diabetes, and to multiple low-dose-streptozotocin (MLDS)-induced hyperglycemia, a model of type 1 diabetes (T1D). To investigate whether the effects of mTORC1 activation by Rheb in B6(Rheb) mice would also be evident in NOD mice, a spontaneous autoimmune T1D model, we created two NOD mouse lines overexpressing Rheb in their ß-cells (NOD(Rheb); R3 and R20). We verified Rheb overexpression in ß-cells, the relative activation of mTORC1 and ß-cell enlargement. By 35 weeks of age, diabetes incidence was significantly greater in the R3 line and tended to be greater in the R20 line than in NOD mice. Histological analysis demonstrated that insulitis was significantly accelerated in 12-week-old R3 NOD(Rheb) mice compared with NOD mice. Furthermore, serum insulin autoantibody (IAA) expression was significantly higher than that of NOD mice. We also examined whether complete Freund's adjuvant (CFA) treatment alone or with glucagon-like peptide-1 (GLP-1) analog would reverse the hyperglycemia of NOD(Rheb) mice; unexpectedly, almost none achieved normoglycemia. In summary, diabetes progression was significantly accelerated rather than prevented in NOD(Rheb) mice. Our results suggest that the ß-cell enlargement might merely enhance the autoimmunity of pathogenic T-cells against islets, leading to acceleration of autoimmune diabetes. We conclude that not only enlargement but also regeneration of ß-cells in addition to the prevention of ß-cell destruction will be required for the ideal therapy of autoimmune T1D.
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Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Proteínas de Unión al GTP Monoméricas/genética , Neuropéptidos/genética , Proteínas/metabolismo , Animales , Diabetes Mellitus Tipo 1/metabolismo , Progresión de la Enfermedad , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Congénicos , Ratones Endogámicos NOD , Complejos Multiproteicos , Proteína Homóloga de Ras Enriquecida en el Cerebro , Serina-Treonina Quinasas TORRESUMEN
The transcription factor sterol regulatory element-binding protein 1c (SREBP1c) plays an important role in the control of fatty acid metabolism in the liver. Evidence suggests that mammalian target of rapamycin (mTOR) complex 1 (mTORC1) contributes to the regulation of SREBP1c expression, but signaling downstream of mTORC1 remains unclear. We have now shown that medium rich in branched-chain amino acids stimulates expression of the SREBP1c gene in cultured hepatocytes in a manner sensitive both to rapamycin, a pharmacological inhibitor of mTORC1, and to a short hairpin RNA (shRNA) specific for S6 kinase 1 (S6K1), a downstream effector of mTORC1. The phosphorylation of S6K1 was increased in the liver of obese db/db mice. Furthermore, depletion of hepatic S6K1 in db/db mice with the use of an adenovirus vector encoding S6K1 shRNA resulted in down-regulation of SREBP1c gene expression in the liver as well as a reduced hepatic triglyceride content and serum triglyceride concentration. These results thus suggest that S6K1 regulates SREBP1c expression both in cultured hepatocytes and in mouse liver, and that increased hepatic activity of S6K1 contributes at least in part to the pathogenesis of obesity-induced hepatic steatosis and hypertriglyceridemia.
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Regulación de la Expresión Génica , Hígado/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Animales , Línea Celular , Cromonas/farmacología , Hígado Graso/genética , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hipertrigliceridemia/genética , Hígado/efectos de los fármacos , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Endogámicos , Morfolinas/farmacología , Complejos Multiproteicos , Obesidad/genética , Obesidad/metabolismo , Proteínas/antagonistas & inhibidores , Proteínas/metabolismo , ARN Interferente Pequeño/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Sirolimus/farmacología , Serina-Treonina Quinasas TORRESUMEN
BACKGROUND: The authors report a case in which mechanical thrombectomy and carotid artery stenting (CAS) were performed for acute cerebral infarction with free-floating thrombosis (FFT) in left internal carotid artery (ICA) stenosis. Good results were obtained. OBSERVATIONS: A 63-year-old man developed sudden disturbance of consciousness and right hemiplegia. He was transported to the authors' hospital by an emergency vehicle. Head magnetic resonance imaging showed acute cerebral infarction in the left middle cerebral artery region, and magnetic resonance angiography showed poor vascular flow beyond the left ICA. Emergency angiography revealed severe stenosis at the origin of the left ICA and a free-floating thrombus attached to the stenosis and extending to the peripheral side. Percutaneous transluminal angioplasty (PTA) was performed on the stenosis with proximal protection, the thrombus was aspirated under reversal flow, and CAS was performed without exacerbation of clinical symptoms. LESSONS: PTA, thrombus aspiration, and CAS under reversal flow may be effective treatments for FFT caused by ICA stenosis.
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This study aimed to investigate whether the Kenyan Food Pyramid (FP) can evaluate excess or insufficient nutrient intake. Participants were farmers (56 men and 64 women, aged 18-60 years) in Wangige Village, Kiambu County-a peri-urban area of Kenya. Cross-sectional data were collected for demographic characteristics, physical measurements, and 2-day and 24-h dietary recalls. The average adherence level to the FP (hereafter, "FP score") was 25.0 out of 50.0, with a minimum and maximum of 14.1 and 41.5, respectively. Energy and protein % energy ratio were significantly higher (p for trend < 0.05) in the higher FP score group. A higher FP score was also associated with a higher energy-adjusted micronutrient intake, and it was more likely to meet nutrient requirements. However, the higher FP score group had a higher risk of excess sodium intake (p for trend < 0.001). The Kenyan FP could be a useful tool for avoiding the risk of insufficient nutrient intake, but not for avoiding high energy and sodium intake. It is necessary to include appropriate evaluations to limit energy, sugar, and salt. Food groups and recommendations of the FP should be optimised according to the dietary environment of the target population so as to promote their health.
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Dieta/normas , Necesidades Nutricionales , Estado Nutricional , Adulto , Estudios Transversales , Ingestión de Alimentos , Agricultores , Femenino , Humanos , Kenia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Población UrbanaRESUMEN
BACKGROUND: Coronary artery disease is a leading cause of morbidity and mortality among patients with diabetes. Previously, we demonstrated that branched-chain amino acids (BCAAs) showed cardioprotective effects against cardiac ischemia/reperfusion (I/R) injury. A recent study suggested that leucine (Leu), a BCAA, is a key amino acid involved in mammalian target of rapamycin (mTOR) activity and mitochondrial function. However, whether Leu has cardioprotective effects on diabetic hearts is unclear. In this study, we examined the preconditioning effect of Leu treatment on high-fat diet (HFD)-induced obese mouse which simulate prediabetic heart. METHODS: In vivo mice models of I/R injury were divided into the following groups: control, mTOR+/-, and high-fat diet (HFD)-induced obese groups. Mice were randomly administered with Leu, the mTOR inhibitor rapamycin (Rap), or Leu with Rap. Isolated rat cardiomyocytes were subjected to simulated I/R injury. Biochemical and mitochondrial functional assays were performed to evaluate the changes in mTOR activity and mitochondrial dynamics caused by Leu treatment. RESULTS: Leu-treated mice showed a significant reduction in infarct size when compared with the control group (34.8% ± 3.8% vs. 43.1% ± 2.4%, n = 7, p < 0.05), whereas Rap-treated mice did not show the protective effects of Leu. This preconditioning effect of Leu was attenuated in mTOR+/- mice. Additionally, Leu increased the percentage of fused mitochondria and the mitochondrial volume, and decreased the number of mitochondria per cell in isolated cardiomyocytes. In HFD-induced obese mice, Leu treatment significantly reduced infarct size (41.0% ± 1.1% vs. 51.0% ± 1.4%, n = 7, p < 0.05), which was not induced by ischemic preconditioning, and this effect was inhibited by Rap. Furthermore, we observed enhanced mTOR protein expression and mitochondrial fusion with decreased reactive oxygen species production with Leu treatment in HFD-induced obese mice, but not in mTOR+/- mice. CONCLUSIONS: Leu treatment improved the damage caused by myocardial I/R injury by promoting mTOR activity and mitochondrial fusion on prediabetic hearts in mice.
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Sodium-glucose cotransporter 2 (SGLT2) inhibitors often increase the hematocrit. It remains unclear whether this increase would be observed in all patients administered SGLT2 inhibitors, however. We therefore used the data from the previous study and investigated time-dependent alterations of various outcomes related to erythrocytes, erythropoiesis, and clinical outcome in type 2 diabetes subjects (n = 89) treated with ipragliflozin for 16 weeks. Among a total of 89 participants, 71 subjects (80.0% of total participants) showed the elevation of the hematocrit and 18 subjects (20.0% of total participants) did not at 16 weeks. Although the hematocrit levels at baseline were significantly lower in hematocrit-elevated group than non-elevated group, they reached the same levels 4 weeks after the onset of treatment. Binomial logistic regression analysis demonstrated that a lower baseline hematocrit level was related to the elevation of hematocrit at 16 weeks. Optimal cutoff hematocrit levels at baseline to predict hematocrit elevation were 46.9% (male) and 41.7% (female) in ROC analysis. Random intercept model analysis revealed the serum erythropoietin level increased in both hematocrit-elevated and non-elevated groups, whereas only the former group showed an increase in the percentage of reticulocytes during the first 4 weeks. These results suggest that the ipragliflozin-induced increase in hematocrit which is affected by the baseline hematocrit level is attributable to the responsiveness to, but not to the production of, erythropoietin. Collectively, Ht elevation observed in administration of SGLT2 inhibitors can result from erythropoietin-induced erythropoiesis, which is determined by the pre-treatment Ht level. Trial registration: This trial has been registered with University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR no. 000015478).
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Previous studies have suggested that inhibition of the mammalian target of rapamycin (mTOR) by rapamycin suppresses myocardial hypertrophy. However, the role of mTOR in the progression of cardiac dysfunction in pathological hypertrophy has not been fully defined. Interestingly, recent reports indicate that the inflammatory response, which plays an important role in the development of heart failure, is enhanced by rapamycin under certain conditions. Our aim in this study was to determine the influence of mTOR on pathological hypertrophy and to assess whether cardiac mTOR regulates the inflammatory response. We generated transgenic mice with cardiac-specific overexpression of wild-type mTOR (mTOR-Tg). mTOR-Tg mice were protected against cardiac dysfunction following left ventricular pressure overload induced by transverse aortic constriction (TAC) (P < 0.01) and had significantly less interstitial fibrosis compared with littermate controls (WT) at 4 wk post-TAC (P < 0.01). In contrast, TAC caused cardiac dysfunction in WT. At 1 wk post-TAC, the proinflammatory cytokines interleukin (IL)-1ß and IL-6 were significantly increased in WT mice but not in mTOR-Tg mice. To further characterize the effects of mTOR activation, we exposed HL-1 cardiomyocytes transfected with mTOR to lipopolysaccharide (LPS). mTOR overexpression suppressed LPS-induced secretion of IL-6 (P < 0.001), and the mTOR inhibitors rapamycin and PP242 abolished this inhibitory effect of mTOR. In addition, mTOR overexpression reduced NF-κB-regulated transcription in HL-1 cells. These data suggest that mTOR mitigates adverse outcomes of pressure overload and that this cardioprotective effect of mTOR is mediated by regulation of the inflammatory reaction.
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Cardiomegalia/fisiopatología , Corazón/fisiopatología , Miocitos Cardíacos/enzimología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Cardiomegalia/enzimología , Cardiomegalia/patología , Femenino , Humanos , Inflamación/enzimología , Inflamación/genética , Inflamación/patología , Interleucina-1beta/análisis , Interleucina-6/análisis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Miocitos Cardíacos/patología , Ratas , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Antigen-specific immunotherapy is expected to be an ideal strategy for treating type 1 diabetes (T1D). We investigated the therapeutic efficacy of a peptide in the leader sequence of preproinsulin, which was selected because of its binding affinity to the MHC I-A(g7) molecule. Preproinsulin-1 L7-24 peptide (L7-24) emulsified in Freund's incomplete adjuvant was administered subcutaneously to NOD mice. Administration of L7-24 increased the proportion of regulatory T cells in the spleen. Splenocytes of NOD mice immunized with this peptide secreted IL-4 and IL-10 in response to L7-24. This peptide also significantly prevented the development of diabetes and cured some newly diabetic NOD mice without recurrence. L7-24 peptide, which has a high affinity for pockets of I-A(g7), induced regulatory T cells and showed therapeutic effects. This peptide may provide a new approach for developing antigen-specific immunotherapy for autoimmune diabetes.
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Autoinmunidad/inmunología , Diabetes Mellitus Tipo 1/terapia , Inmunoterapia Activa/métodos , Insulina/inmunología , Islotes Pancreáticos/inmunología , Fragmentos de Péptidos/inmunología , Precursores de Proteínas/inmunología , Linfocitos T Reguladores/inmunología , Secuencia de Aminoácidos , Animales , Glucemia/inmunología , Glucemia/metabolismo , Recuento de Células , Concanavalina A/farmacología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/prevención & control , Femenino , Factores de Transcripción Forkhead/metabolismo , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Insulina/genética , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Islotes Pancreáticos/citología , Islotes Pancreáticos/patología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/uso terapéutico , Unión Proteica/inmunología , Bazo/citología , Bazo/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , VacunaciónRESUMEN
Antigen-specific regulatory CD4(+) T cells have been described but there are few reports on regulatory CD8(+) T cells. We generated islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific regulatory CD8(+) T cells from 8.3-NOD transgenic mice. CD8(+) T cells from 8.3-NOD splenocytes were cultured with IGRP, splenic dendritic cells (SpDCs), TGF-beta, and all-trans retinoic acid (ATRA) for 5days. CD8(+) T cells cultured with either IGRP alone or IGRP and SpDCs in the absence of TGF-beta and ATRA had low Foxp3(+) expression (1.7+/-0.9% and 3.2+/-4.5%, respectively). In contrast, CD8(+) T cells induced by exposure to IGRP, SpDCs, TGF-beta, and ATRA showed the highest expression of Foxp3(+) in IGRP-reactive CD8(+) T cells (36.1+/-10.6%), which was approximately 40-fold increase compared with that before induction culture. CD25 expression on CD8(+) T cells cultured with IGRP, SpDCs, TGF-beta, and ATRA was only 7.42%, whereas CD103 expression was greater than 90%. These CD8(+) T cells suppressed the proliferation of diabetogenic CD8(+) T cells from 8.3-NOD splenocytes in vitro and completely prevented diabetes onset in NOD-scid mice in cotransfer experiments with diabetogenic splenocytes from NOD mice in vivo. Here we show that exposure to ATRA and TGF-beta induces CD8(+)Foxp3(+) T cells ex vivo, which suppress diabetogenic T cells in vitro and in vivo.
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Linfocitos T CD8-positivos/efectos de los fármacos , Diabetes Mellitus Tipo 1/prevención & control , Linfocitos T Reguladores/efectos de los fármacos , Factor de Crecimiento Transformador beta/farmacología , Tretinoina/farmacología , Animales , Linfocitos T CD8-positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Factores de Transcripción Forkhead/metabolismo , Glucosa-6-Fosfatasa/genética , Glucosa-6-Fosfatasa/inmunología , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , Proteínas/genética , Proteínas/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
An 84-year-old man developed motor aphasia and right hemiparesis on postoperative day 1 after orchiectomy for suspected malignant lymphoma. He had a history of thoracic endovascular aortic repair for aortic aneurysm using a bypass graft from the right subclavian artery to the left common carotid artery (CCA); however, the graft had become occluded six months later. Brain magnetic resonance imaging revealed acute cerebral infarctions in the left frontal lobe. Carotid ultrasonography revealed a stump at the left CCA, just below the bifurcation, formed by the occluded graft with an oscillating thrombus. This case was rare in that a CCA stump was identified as the embolic source of ischemic stroke.
Asunto(s)
Arteria Carótida Común/patología , Accidente Cerebrovascular Isquémico/etiología , Anciano de 80 o más Años , Procedimientos Endovasculares/métodos , Humanos , Masculino , TrombosisRESUMEN
A 42-year-old man was hospitalized due to a fever, orchiodynia, and extremely severe myalgia predominantly in the extremities, which made it difficult for him to stand or walk. He had a history of contact with his son who had acute upper respiratory infection. Based on the characteristic clinical symptoms and detection of the partial sequence of human parechovirus type 3 (HPeV3) in throat swabs as well as stool and serum samples, he was diagnosed with epidemic myalgia associated with HPeV3 infection. Because HPeV3 infection is widespread among children in Japan, HPeV3-associated myalgia should be considered when adult patients manifest such distinguishing clinical characteristics.