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Adipose-derived stem cell (ASC)-released exosomes (ASCexos) have multiple biological activities. We examined the effect of ASCexos derived from the inguinal adipose tissue of exercise-trained rats (EX-ASCexos) on adipogenic conversion of 3T3-L1 cells and analyzed their microRNA (miRNA) expression profiles. Differentiation of 3T3-L1 cells into adipocytes was performed for 9 d with EX-ASCexos or ASCexos from sedentary control rats (SED-ASCexos), and the expression of proteins and miRNA involved in adipogenic differentiation were determined. EX-ASCexos but not SED-ASCexos attenuated 3T3-L1 adipocyte differentiation with increased phosph-Ser112PPARγ expression, the inactive form of PPARγ. These differentiated adipocytes were also accompanied by increased phosph-Thr202/Tyr204ERK and decreased dual-specificity phosphatase 3 (DUSP3) levels. The exosomal miRNAs miR-323-5p, miR-433-3p, and miR-874-3p were identified specifically in EX-ASCexos. Of these, miR-323-5p mimic replicated the EX-ASCexo-induced suppression of 3T3-L1 adipocyte differentiation and altered adipogenesis-related factor expression. In conclusion, exercise training-driven exosomal miR-323-5p suppressed 3T3-L1 adipogenesis by increasing phosph-Ser112PPARγ expression, while phosph-Thr202/Tyr204ERK accumulation inhibited DUSP3 expression.
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Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased platelet destruction and impaired platelet production from bone marrow megakaryocytes. The details of different platelet destruction mechanisms resulting from differences in autoantibodies and autoantibody-independent direct platelet destruction remain unclear although antiplatelet autoantibodies directed against platelet glycoproteins, such as GPIIb/IIIa and GPIb, play a central role in ITP pathogenesis. ITP is diagnosed by excluding other causes of thrombocytopenia due to the lack of standard tests or biomarkers for its confirmation. Plasma thrombopoietin level measurement and reticulated platelet ratio are useful in distinguishing the cause of thrombocytopenia and will be included in the new "Diagnostic reference guide of adult immune thrombocytopenia." Currently, the treatment of refractory chronic ITP is mainly based on thrombopoietin receptor agonists, but ITP drugs with novel mechanisms of action are actively developed. New therapeutic agents are expected to be selected based on an accurate diagnosis and tailored to the pathophysiology of each case in ITP treatment.
Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Adulto , Humanos , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Plaquetas , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , AutoanticorposRESUMO
NEW FINDINGS: What is the central question of this study? Exercise can stimulate brown adipose tissue (BAT) with subsequent increase in uncoupling protein 1 expression and mitochondrial biogenesis. In that case, do BAT-specific Hox genes modify BAT functioning and cause uncoupling protein expression changes due to exercise? What is the main finding and its importance? Exercise enhanced brown adipocyte markers, with significant upregulation of HoxA5 and downregulation of HoxC10 mRNA expression in rat BAT. HoxA5 and HoxC10 are thus likely to play distinct roles in exercise-induced changes in BAT markers during the early postnatal period. These findings provide new insight into the mechanisms underlying exercise-induced changes in BAT function. ABSTRACT: Brown adipose tissue (BAT) recruitment is involved in increased energy expenditure associated with cold exposure and exercise training. We explored whether exercise training induced changes in expression levels of brown adipocyte-selective factors and Homeobox (Hox) genes during the post-weaning growth period of male Wistar rats. Relative to total body weight, BAT weights alone were lower in exercise-trained (EX) rats compared to sedentary control (SED) rats. mRNA expression of HoxA5 was higher and that of HoxC10 was lower in EX rats than in SED rats, accompanied by both higher citrate synthase activity and protein expression levels for uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor (PPAR) α, and PPARγ-coactivator (PGC)-1α. HoxA5 knockdown with siRNA reduced the expression of PR-domain containing 16 (Prdm16), cell death-inducing DNA fragmentation factor-α-like effector A (Cidea) gene, type 2 deiodinase mRNA, and PRDM16 protein. Comparatively, HoxC10 knockdown with siRNA enhanced mRNA expression of Prdm16, Pparα and Pgc1α and protein expression of UCP1, PPARα and PGC1α in brown adipocytes. The stimulation of brown adipocytes with isoproterenol, a ß-adrenoceptor agonist, caused a phenomenon similar to the effect of exercise training on the genes tested: upregulation of HoxA5 mRNA, downregulation of HoxC10 mRNA, and increased protein expression for UCP1 and PGC1α. Collectively, HoxA5 and HoxC10 may have unique functions that contribute to modulating the expression of BAT-selective markers in BAT of juvenile rats during exercise training. The study findings regarding activation and recruitment of BAT during exercise training have implications for anti-obesity management.
Assuntos
Adaptação Fisiológica/genética , Tecido Adiposo Marrom/metabolismo , Genes Homeobox/genética , Proteínas de Homeodomínio/genética , Condicionamento Físico Animal/fisiologia , Animais , Citrato (si)-Sintase/metabolismo , Proteínas de Homeodomínio/metabolismo , Masculino , PPAR alfa/genética , PPAR alfa/metabolismo , Ratos , Ratos Wistar , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
Controlling the differentiation potential of adipose-derived stem cells (ADSCs) is attracting attention as a new strategy for the prevention and treatment of obesity. Here, we aimed to observe the effect of exercise training (TR) and high-fat diet (HFD) on the metabolic profiles of ADSCs-derived adipocytes. The rats were divided into four groups: normal diet (ND)-fed control (ND-SED), ND-fed TR (ND-TR), HFD-fed control (HFD-SED), and HFD-fed TR (HFD-TR). After 9 weeks of intervention, ADSCs of epididymal and inguinal adipose tissues were differentiated into adipocytes. In the metabolome analysis of adipocytes after isoproterenol stimulation, 116 metabolites were detected. The principal component analysis demonstrated that ADSCs-derived adipocytes segregated into four clusters in each fat pad. Amino acid accumulation was greater in epididymal ADSCs-derived adipocytes of ND-TR and HFD-TR, but lower in inguinal ADSCs-derived adipocytes of ND-TR, than in the respective controls. HFD accumulated several metabolites including amino acids in inguinal ADSCs-derived adipocytes and more other metabolites in epididymal ones. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that TR mainly affected the pathways related to amino acid metabolism, except in inguinal ADSCs-derived adipocytes of HFD-TR rats. These findings provide a new way to understand the mechanisms underlying possible changes in the differentiation of ADSCs due to TR or HFD.
Assuntos
Adipócitos/metabolismo , Dieta Hiperlipídica , Metaboloma , Condicionamento Físico Animal/fisiologia , Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Adipogenia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Gorduras na Dieta/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Metaboloma/efeitos dos fármacos , Cultura Primária de Células , Ratos , Gordura Subcutânea/citologia , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismoRESUMO
Platelet function of immune thrombocytopenia (ITP) has been controversial because of methodological problems associated with low platelet counts. In this study, we evaluated platelet function in 21 patients with chronic ITP (cITP) using the recently developed flow cytometry (FCM)-based platelet aggregation assay (FCA) along with a PAC1/CD62P assay. Since ITP platelets are larger than controls, whole platelets (whole gating method) and size-adjusted platelets (size-adjusted method) were analysed in the PAC1/CD62P via FCM. We found that: (i) aggregation was equivalent [phorbol myristate acetate (PMA) or adenosine diphosphate (ADP)-induced] or enhanced [protease-activated receptor 1-activating peptide (PAR1AP)-induced] in cITP compared with control by FCA; (ii) PAC1 or CD62P was also equivalent or enhanced in cITP in the whole gating method; and (iii) in sharp contrast, the size-adjusted method revealed that ADP-, PAR1AP-, and collagen synthetic liquid reactive peptide (SRP)-induced PAC1 and ADP-induced CD62P were impaired in cITP. These data suggested that an increase in the number of larger-sized platelets may compensate for the impaired platelet function of cITP, leading to non-inferiority of overall platelet function in cITP. Furthermore, we revealed that ADP-induced aggregation was impaired in the patients with thrombopoietin receptor agonists (TPO-RAs) or platelet-associated anti-αIIbß3 antibodies compared with the control, suggesting that the presence of anti-αIIbß3 autoantibodies and/or administration of TPO-RAs may have a negative impact on platelet function.
Assuntos
Plaquetas/imunologia , Testes de Função Plaquetária/métodos , Púrpura Trombocitopênica Idiopática/sangue , Receptores de Trombopoetina/agonistas , Idoso , Anticorpos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Exercise training is well known to enhance adipocyte lipolysis in response to hormone challenge. However, the existence of a relationship between the timing of exercise training and its effect on adipocyte lipolysis is unknown. To clarify this issue, Wistar rats were run on a treadmill for 9 weeks in either the early part (E-EX) or late part of the active phase (L-EX). L-EX rats exhibited greater isoproterenol-stimulated lipolysis expressed as fold induction over basal lipolysis, with greater protein expression levels of hormone-sensitive lipase (HSL) phosphorylated at Ser 660 compared to E-EX rats. Furthermore, we discovered that Brain and muscle Arnt-like (BMAL)1 protein can associate directly with several protein kinase A (PKA) regulatory units (RIα, RIß, and RIIß) of protein kinase, its anchoring protein (AKAP)150, and HSL, and that the association of BMAL1 with the regulatory subunits of PKA, AKAP150, and HSL was greater in L-EX than in E-EX rats. In contrast, comparison between E-EX and their counterpart sedentary control rats showed a greater co-immunoprecipitation only between BMAL1 and ATGL. Thus, both E-EX and L-EX showed an enhanced lipolytic response to isoproterenol, but the mechanisms underlying exercise training-enhanced lipolytic response to isoproterenol were different in each group.
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Isoproterenol/farmacologia , Lipólise/efeitos dos fármacos , Condicionamento Físico Animal , Esterol Esterase/metabolismo , Proteínas de Ancoragem à Quinase A/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Adipose-derived stem cells (ADSCs) can differentiate into neurons under particular conditions. It remains largely unknown whether this differentiation potential is affected by physical conditions such as obesity, which modulates the functions of adipose tissue. In this study, we determined the impact of either a 9-week high-fat diet (60% fat; HFD) or 9-week exercise training on the differentiation potential of ADSCs into neuron-like cells in male Wistar rats. Rats were randomly assigned to a normal diet-fed (ND-SED) group, HFD-fed (HFD-SED) group, or exercise-trained HFD-fed group (HFD-EX). After a 9-week intervention, ADSCs from all groups differentiated into neuron-like cells. Expression of neuronal marker proteins (nestin, ßIII-tubulin, and microtubule-associated protein 2 [MAP2]) and the average length of cell neurites were lower in cells from HFD-SED rats than in other groups. Instead, protein expression of COX IV and Cyt-c, the Bax/Bcl-2 and LC3-II/I ratio, and the malondialdehyde level in culture medium were higher in cells from HFD-SED rats. No significant difference between ND-SED and HFD-EX rats was observed, except for the average length of cell neurites in MAP2. Thus, HFD impaired the differentiation potential of ADSCs into neuron-like cells, which was accompanied by increases in apoptotic activity and oxidative stress. Importantly, exercise training ameliorated the HFD-induced impairment of neurogenesis in ADSCs. The adipose tissue microenvironment could influence the differentiation potential of ADSCs, a source of autologous stem cell therapy.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Células-Tronco Neurais/patologia , Neurogênese , Neurônios/patologia , Estresse Oxidativo , Condicionamento Físico Animal , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia , Proteínas Relacionadas à Autofagia/metabolismo , Linhagem da Célula , Células Cultivadas , Microambiente Celular , Masculino , Proteínas Mitocondriais/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Neuritos/metabolismo , Neuritos/patologia , Neurônios/metabolismo , Ratos Wistar , CorridaRESUMO
Affinity regulation of integrin αIIbß3 for fibrinogen by inside-out signaling plays a critical role in hemostasis. Calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) was identified as a Rap1-activating molecule, and its role in inside-out αIIbß3 activation was established in CalDAG-GEFI-deficient mice. However, little information regarding CalDAG-GEFI in human platelets is available. Here, we report a 16-year-old girl with CalDAG-GEFI deficiency who has been suffering from severe bleeding tendency. Although talin and kindlin-3 were normally detected, CalDAG-GEFI was undetectable in her platelets by western blotting. Genetic analysis revealed compound heterozygous CalDAG-GEFI mutations, Lys309X and Leu360del, which were responsible for CalDAG-GEFI deficiency. The functional analysis demonstrated impaired αIIbß3 activation by various agonists except for phorbol myristate acetate, normal calcium mobilization, and impaired Rap1 activation, which were consistent with the phenotype of CalDAG-GEFI-deficient mice. Despite substantial αIIbß3 activation at high agonist concentrations, she had severe bleeding tendency. Further functional analysis demonstrated markedly delayed αIIbß3 activation velocity and decreased shear-induced thrombus formation. Contrary to CalDAG-GEFI-deficient mice, which showed integrin-dependent neutrophil functional abnormality, neutrophil ß2 integrin activation was not impaired in the patient. Our results demonstrate the critical role of CalDAG-GEFI in rapid αIIbß3 activation of human platelets.
Assuntos
Plaquetas/metabolismo , Fatores de Troca do Nucleotídeo Guanina/deficiência , Hemorragia , Mutação de Sentido Incorreto , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Adolescente , Substituição de Aminoácidos , Animais , Plaquetas/patologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Hemorragia/genética , Hemorragia/metabolismo , Hemorragia/patologia , Humanos , Camundongos , Camundongos Knockout , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genéticaRESUMO
OBJECTIVE: Wernicke's encephalopathy (WE) is a neuropsychiatric disorder caused by a thiamine deficiency. Although WE has been recognized in cancer patients, it can be overlooked because many patients do not exhibit symptoms that are typical of WE, such as delirium, ataxia, or ocular palsy. Furthermore, outpatients with WE who intermittently present at psycho-oncology clinics have not been described as far as we can ascertain. METHOD: This report describes two patients who did not exhibit the complete classic triad of symptoms among a series with cancer and WE, and who attended a psycho-oncology outpatient clinic.ResultCase 1, a 76-year-old woman with pancreatic cancer and liver metastasis, periodically attended a psycho-oncology outpatient clinic. She presented with delirium and ataxia as well as appetite loss that had persisted for 8 weeks. We suspected WE, which was confirmed by low serum thiamine levels and the disappearance of delirium after thiamine administration. Case 2, a 79-year-old man with advanced stomach cancer, was referred to a psycho-oncology outpatient clinic with depression that had persisted for about 1 month. He also had appetite loss that had persisted for several weeks. He became delirious during the first visit to the outpatient clinic. Our initial suspicion of WE was confirmed by low serum thiamine levels and the disappearance of delirium after thiamine administration. The key indicator of a diagnosis of WE in both patients was appetite loss.Significance of resultsThis report emphasizes awareness of WE in the outpatient setting, even when patients do not exhibit the classical triad of WE. Appetite loss might be the key to a diagnosis of WE in the absence of other causes of delirium.
Assuntos
Diagnóstico Precoce , Pacientes Ambulatoriais/estatística & dados numéricos , Encefalopatia de Wernicke/diagnóstico , Idoso , Instituições de Assistência Ambulatorial/organização & administração , Delírio/etiologia , Feminino , Humanos , Masculino , Psico-Oncologia/métodos , Encefalopatia de Wernicke/terapiaRESUMO
The bidirectional signaling and hemostatic functions of platelet αIIbß3 are regulated by kindlin-3 through interactions with the ß3 cytoplasmic tail. Little is known about kindlin regulation of the related "vitronectin receptor," αVß3. These relationships were investigated in endothelial cells, which express αVß3 and kindlin-2 endogenously. "ß3ΔRGT" knock-in mice lack the 3 C-terminal ß3 tail residues, whereas in "ß3/ß1(EGK)" mice, RGT is replaced by the corresponding residues of ß1. The wild-type ß3 tail pulled down kindlin-2 and c-Src in vitro, whereas ß3ΔRGT bound neither protein and ß3/ß1(EGK) bound kindlin-2, but not c-Src. ß3ΔRGT endothelial cells, but not ß3/ß1(EGK) endothelial cells, exhibited migration and spreading defects on vitronectin and reduced sprouting in 3-dimensional fibrin. Short hairpin RNA silencing of kindlin-2, but not c-Src, blocked sprouting by ß3 wild-type endothelial cells. Moreover, defective sprouting by ß3ΔRGT endothelial cells could be rescued by conditional, forced interaction of αVß3ΔRGT with kindlin-2. Stimulation of ß3ΔRGT endothelial cells led to normal extracellular ligand binding to αVß3, pin-pointing their defect to one of outside-in αVß3 signaling. ß3ΔRGT mice, but not ß3/ß1(EGK) mice, exhibited defects in both developmental and tumor angiogenesis, responses that require endothelial cell function. Thus, the ß3/kindlin-2 interaction promotes outside-in αVß3 signaling selectively, with biological consequences in vivo.
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Proteínas do Citoesqueleto/metabolismo , Integrina alfaVbeta3/metabolismo , Integrina beta3/metabolismo , Proteínas Musculares/metabolismo , Animais , Plaquetas/metabolismo , Transplante de Medula Óssea , Movimento Celular , Citoplasma/metabolismo , Células Endoteliais , Humanos , Melanoma Experimental , Proteínas de Membrana/metabolismo , Camundongos , Mutação , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Neovascularização Patológica , Ligação Proteica , Estrutura Terciária de Proteína , Interferência de RNA , Transdução de SinaisRESUMO
Platelets are critical for hemostasis and genetic defects involving platelet functions result in symptomatic bleeding of varying severities. In contrast to platelet quantitative disorders, qualitative platelet disorders are relatively rare and are difficult to diagnose, especially in patients with mild bleeding symptoms due to their lack of specificity for platelet dysfunction. In addition, the lack of standard platelet function tests makes it difficult for physicians to clinically distinguish patients from healthy subjects and, on occasion, the cause of bleeding symptoms remains unspecified. Resting platelets in the circulation become activated for thrombus formation at the site of vascular injury. Thrombus formation consists of platelet adhesion, granule secretion, and aggregate formation. An abnormality in any of the steps of thrombus formation has the potential to cause platelet dysfunction and bleeding symptoms. Understanding the mechanism of thrombus formation and the laboratory tests for evaluation of each step is important for properly diagnosing platelet function disorders.
Assuntos
Transtornos Hemorrágicos , Transtornos da Coagulação Sanguínea , Transtornos Plaquetários , Plaquetas/fisiologia , Humanos , Agregação Plaquetária , Transdução de SinaisRESUMO
The purpose of this study was to uncover the effect of exercise training on the expression of autophagy marker proteins in epididymal white adipose tissue (eWAT), inguinal WAT (iWAT), and the stromal vascular fraction (SVF) collected from eWAT. Male Wistar rats aged 4-5 weeks were randomly divided into two groups, sedentary control (n = 7) and exercise-trained (n = 7). Rats in the exercise-trained group were exercised on a treadmill set at a 5° incline 5 days/week for 9 weeks. We determined that the expression levels of an autophagosome-associating form of microtubule-associated protein 1 light chain 3 (LC3)-II and of p62 were significantly higher in eWAT from exercise-trained than from control rats, while those of adipose-specific deletion of autophagy-related protein (ATG7) and lysosomal-associated membrane protein type 2A (LAMP2a) showed no difference between groups. However, in iWAT, the expression levels of LC3-II and ATG7 were significantly higher in exercise-trained than in control rats. The expression of p62 was highly correlated with that of peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and lipid metabolism, in both WAT types (eWAT, r = 0.856, P < 0.05; iWAT, r = 0.762, P < 0.05), whereas LC3-II and PPARγ levels were highly correlated in eWAT (r = 0.765, P < 0.05) but not in iWAT (r = -0.306, ns). In SVF, the expression levels of LC3II, ATG7, and LAMP2a were significantly higher in exercise-trained than in control rats. These results suggest that exercise training suppresses basal autophagy activity in eWAT, but that this activity is enhanced in iWAT and SVF collected from eWAT. Thus, the adaptation of basal autophagic activity following exercise training exhibits fat depot-specific differences.
Assuntos
Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/fisiologia , Autofagia/fisiologia , Condicionamento Físico Animal/fisiologia , Adaptação Fisiológica , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Proteína 7 Relacionada à Autofagia , Biomarcadores/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , PPAR gama/metabolismo , Resistência Física/fisiologia , Ratos , Ratos Wistar , Proteína Sequestossoma-1 , Enzimas Ativadoras de Ubiquitina/metabolismoRESUMO
Melatonin is synthesized in the pineal gland, but elicits a wide range of physiological responses in peripheral target tissues. Recent advances suggest that melatonin controls adiposity, resulting in changes in body weight. The aim of this study was to investigate the effect of melatonin on adipogenesis and mitochondrial biogenesis in 3T3-L1 mouse embryo fibroblasts. Melatonin significantly increased the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a master regulator of adipogenesis, and promoted differentiation into adipocytes. Melatonin-treated cells also formed smaller lipid droplets and abundantly expressed several molecules associated with lipolysis, including adipose triglyceride lipase, perilipin, and comparative gene identification-58. Moreover, the hormone promoted biogenesis of mitochondria, as indicated by fluorescent staining, elevated the citrate synthase activity, and upregulated the expression of PPAR-γ coactivator 1 α, nuclear respiratory factor-1, and transcription factor A. The expression of uncoupling protein 1 was also observable both at mRNA and at protein level in melatonin-treated cells. Finally, adiponectin secretion and the expression of adiponectin receptors were enhanced. These results suggest that melatonin promotes adipogenesis, lipolysis, mitochondrial biogenesis, and adiponectin secretion. Thus, melatonin has potential as an anti-obesity agent that may reverse obesity-related disorders.
Assuntos
Adipogenia/efeitos dos fármacos , Melatonina/farmacologia , Mitocôndrias/metabolismo , Células 3T3-L1 , Adiponectina/metabolismo , Animais , Lipólise/efeitos dos fármacos , Camundongos , PPAR gama/metabolismoRESUMO
Hyperuricemia is increasing in prevalence and this is paralleled by an increased incidence of acute gout. In addition, there is growing evidence of an association between high serum levels of uric acid (sUA) and cardiovascular disease (CVD). In this preliminary report, we present 12-16 week results from a multicenter, general practice study in which we evaluated the usefulness of febuxostat in a cohort of untreated patients with hyperuricemia with a high prevalence of CVD. Febuxostat titrated from 10 mg/day up to 40 mg/day resulted in statistically significant and clinically relevant reductions in sUA after 12-16 weeks. A "responder" level of 6.0 mg/dL or lower was achieved in 95 of 100 (95%) patients. Significant reductions in sUA were achieved regardless of the presence/absence of coexisting diseases (e.g. CVD, renal insufficiency, diabetes and obesity) or the class of antihypertensive agent being used by the patient. No serious adverse reactions were noted with febuxostat. Although allopurinol has been used generally for hyperuricemia/gout, it is excreted fully via the kidneys, restricting its use in patients with reduced renal function, and its three-times-daily administration leads to poor adherence. Based on the results of this study, febuxostat may provide an easier option than allopurinol for clinicians specializing in CVDs.
Assuntos
Doenças Cardiovasculares/epidemiologia , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Tiazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Relação Dose-Resposta a Droga , Febuxostat , Feminino , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/epidemiologia , Hiperuricemia/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Tiazóis/efeitos adversos , Resultado do Tratamento , Ácido Úrico/sangue , Ácido Úrico/urinaRESUMO
During rugby game, or intensive rugby training there are many high intensity explosive exercises and eccentric muscle contractions, therefore adequate recovery is very important to rugby players. In the present study we have tested the effects of cold water immersion (CWI) after game-simulated (80 min.) rugby training on muscle power recovery and blood markers of muscle damage. Twenty well-trained collegiate male rugby players (age: 20.3 ± 0.6 years old, body height: 1.74 ± 0.05 m, body weight: 85.4 ± 2.0 kg, body fat: 18.2 ± 1.4 %) volunteered for this study. This study was conducted as a cross-over design; i.e., the subjects were randomly assigned either to CWI (n = 10) or passive rest condition (n = 10) for the 1(st) trial and 1 week later the subjects were switched conditions for the 2(nd) trial. After the simulated rugby training, including tackles and body contacts, muscle functional ability and blood markers of muscle damage were tested immediately, after CWI or passive rest, and again 24 hours later. Statistical analysis of all muscle functional tests (10 m dash, counter movement jump, reaction time, side steps) except for 10 seconds maximal pedaling power and blood makers of muscle damage (aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and creatinine) revealed significant main effects for time (p < 0.05). However, no statistically significant interactions were found in any of the muscle functional tests and blood markers between groups and time courses. Our results suggest that a rugby game induces muscle damage and reduces muscle function. However, CWI has no significant restorative effect after an 80-minute rugby game in terms of muscle damage. Key PointsCold water immersion study for the recovery of rugby playersMuscle strength and muscle power were mainly evaluated as well as muscle enzymes of muscle break downSubjects were highly trained rugby players with control group.
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Type 2 diabetes mellitus (T2DM) is an epidemiological risk factor for dementia and has been implicated in multifactorial pathologies, including neuroinflammation. In the present study, we aimed to elucidate the potential anti-inflammatory effects of imeglimin, a novel antidiabetic agent, on high-glucose (HG)-stimulated microglia. Mouse microglial BV2 cells were stimulated with HG in the presence or absence of imeglimin. We examined the effects of imeglimin on the levels of proinflammatory cytokines, intracellular reactive oxygen species (ROS), mitochondrial integrity, and components related to the inflammasome or autophagy pathways in these cells. Our results showed that imeglimin suppressed the HG-induced production of interleukin-1beta (IL-1ß) by reducing the intracellular ROS levels, ameliorating mitochondrial dysfunction, and inhibiting the activation of the thioredoxin-interacting protein (TXNIP)-NOD-like receptor family pyrin domain containing 3 (NLRP3) axis. Moreover, the inhibitory effects of imeglimin on the TXNIP-NLRP3 axis depended on the imeglimin-induced activation of ULK1, which also exhibited novel anti-inflammatory effects without autophagy induction. These findings suggest that imeglimin exerted novel suppressive effects on HG-stimulated microglia through the ULK1-TXNIP-NLRP3 axis, and may, thereby, contribute to the development of innovative strategies to prevent T2DM-associated cognitive impairment.
Assuntos
Diabetes Mellitus Tipo 2 , Triazinas , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/farmacologia , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Tiorredoxinas/efeitos dos fármacos , Tiorredoxinas/metabolismoRESUMO
Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia due to accelerated platelet destruction and impaired platelet production. Diagnosis of ITP is still challenging because ITP has been diagnosed by exclusion. Exclusion of thrombocytopenia due to bone marrow failure is especially important in Japan because of high prevalence of aplastic anemia compared to Western countries. Hence, we propose a new diagnostic criteria involving the measurement of plasma thrombopoietin (TPO) levels and percentage of immature platelet fraction (RP% or IPF%); 1) isolated thrombocytopenia with no morphological evidence of dysplasia in any blood cell type in a blood smear, 2) normal or slightly increased plasma TPO level (< cutoff), 3) elevated RP% or IPF% (> upper limit of normal), and 4) absence of other conditions that potentially cause thrombocytopenia including secondary ITP. A diagnosis of ITP is made if conditions 1-4 are all met. Cases in which criterion 2 or 3 is not met or unavailable are defined as "possible ITP," and diagnosis of ITP can be made mainly by typical clinical course. These new criteria enable us to clearly differentiate ITP from aplastic anemia and other forms of hypoplastic thrombocytopenia and can be highly useful in clinical practice for avoiding unnecessary bone marrow examination as well as for appropriate selection of treatments.
Assuntos
Anemia Aplástica , Leucopenia , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Adulto , Humanos , Anemia Aplástica/diagnóstico , Plaquetas , Trombocitopenia/diagnóstico , Contagem de Plaquetas , TrombopoetinaRESUMO
Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420 mg orally once daily plus weekly rituximab 375 mg/m2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At primary analysis, MRR was 87.5% [14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001 (null hypothesis: 32% response rate)]. At final analysis (median study intervention duration: 34.4 months, median follow-up: 35.0 months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study.
Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Piperidinas , Rituximab , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/mortalidade , Adenina/análogos & derivados , Adenina/administração & dosagem , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Idoso , Pessoa de Meia-Idade , Masculino , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Japão , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Idoso de 80 Anos ou mais , Resultado do Tratamento , Povo Asiático , População do Leste AsiáticoRESUMO
As the number of dementia patients increases, there is a need to protect patients' right to know. However, in reality, there are cases in Japan where spouses' deaths are concealed from patients. We conducted a questionnaire survey of care managers (CMs) to obtain their attitude and actual behavior regarding the disclosure of a spouse's death to patients with dementia. A self-administered, anonymous questionnaire survey was implemented at academic meetings attended by CMs from March to December 2019, inquiring about experiences with spousal deaths of patients with dementia, disclosure rates, behavioral and psychological symptoms of dementia, and depression. Over 80% had experienced the spousal death of a patient with dementia; the percentage of CMs who had implemented the disclosures varied widely. About 18% had experienced worsening behavioral and psychological symptoms of dementia (BPSD), and 26% had worsening depression as a result of the disclosure. About 83% of respondents were positive about disclosure, but about 44% did so less than 50% of the time. This study is the first to reveal the current state of CMs' policies and behaviors regarding the disclosure of spousal death to patients with dementia in Japan. Family members' wishes and the possibility of BPSD put a relatively large number of caregivers in a dilemma regarding disclosure.