RESUMEN
INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown neuroprotective effects in obese mice. However, whether SGLT2i can ameliorate high-fat diet (HFD)-related ovulation disorders remains unknown. The aim of this research was to investigate whether dapagliflozin improves HFD-induced ovulatory dysfunction by attenuating microglia-mediated hypothalamic inflammation. METHODS: C57BL/6J female mice fed HFD were treated with dapagliflozin (1 mg/kg) for 22 weeks. Plasma insulin, leptin, luteinizing hormone (LH), estradiol (E2), and IL-1ß levels were also tested. Microglial morphology, cell numbers, and SGLT2 expression were evaluated using immunofluorescence. The expression of IL-1ß, NLRP3, kisspeptin, gonadotropin-releasing hormone (GnRH), SGLT2, insulin, and leptin receptors in the hypothalamus was determined using immunohistochemical staining. We also examined the effects of dapagliflozin on glucose metabolism and the release of inflammatory factor in palmitic acid (PA)-treated HMC3 cells. RESULTS: As expected, dapagliflozin improved HFD-induced metabolic disturbances, peripheral versus central insulin and leptin resistance and also restored the regular estrous cycle. Furthermore, dapagliflozin blunted microglia activation, NLRP3 inflammasome priming, hypothalamic inflammation, and increased the expression of GnRH and kisspeptin at proestrus in the hypothalamus. Additionally, dapagliflozin markedly reduced IL-6 and NO release and fat accumulation, decreased lactic acid production and glucose consumption, and inhibited mammalian target of rapamycin (mTOR) and hexokinase 2 (HK2) expression in PA-treated HMC3 cells. These effects suggest that dapagliflozin reduced the mTOR/HK2-mediated aerobic glycolysis. CONCLUSIONS: Dapagliflozin improved HFD-related ovulation disorders by regulating glucose metabolism through mTOR/HK2 signaling and attenuating microglia-mediated hypothalamic inflammation. These results validate the novel role for the neuroprotection of SGLT2i in HFD-induced obesity and ovulation disorders.
Asunto(s)
Compuestos de Bencidrilo , Dieta Alta en Grasa , Glucósidos , Leptina , Ratones , Femenino , Animales , Dieta Alta en Grasa/efectos adversos , Leptina/metabolismo , Transportador 2 de Sodio-Glucosa/metabolismo , Transportador 2 de Sodio-Glucosa/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Kisspeptinas/metabolismo , Microglía , Ratones Endogámicos C57BL , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Glucosa/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Ovulación , Mamíferos/metabolismoRESUMEN
This study retrospectively analyzed the clinical outcome of 172 children with newly diagnosed severe aplastic anemia (SAA) between January 2008 and April 2018, who received rabbit antithymocyte globulin (ATG) and cyclosporine (CsA) as first-line treatment. The median age at diagnosis was 5 years (range, 1-14). The overall response rates were 22.7%, 45.3%, and 61% at 40 days, 3 months, and 6 months, respectively, after rabbit ATG. In multivariate analysis, mild disease severity was the only predictor of favorable response at 6 months (P = 0.006). In the present study, median follow-up period was 63 months (range, 1-135). The 5-year overall survival (OS) and failure-free survival (FFS) rates were 90.5% and 70.4%. Multivariate analysis showed that erythroid burst-forming units (BFU-E) > 2/105 bone marrow mononuclear cell (BMMNC) (P = 0.037) and time interval before IST ≤ 30 days (P = 0.017) were independent positive predictors for OS, meanwhile BFU-E > 2/105BMMNC (P = 0.029) was the only favorable prognostic factor for FFS.
Asunto(s)
Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/mortalidad , Suero Antilinfocítico/administración & dosificación , Ciclosporina/administración & dosificación , Inmunosupresores/administración & dosificación , Índice de Severidad de la Enfermedad , Adolescente , Anemia Aplásica/diagnóstico , Animales , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Conejos , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Defects of bone marrow mesenchymal stem cells (BM-MSCs) in proliferation and differentiation are involved in the pathophysiology of aplastic anemia (AA). Infusion of umbilical cord mesenchymal stem cells (UC-MSCs) may improve the efficacy of immunosuppressive therapy (IST) in childhood severe aplastic anemia (SAA). METHODS: We conducted an investigator-initiated, open-label, and prospective phase IV trial to evaluate the safety and efficacy of combination of allogenic UC-MSCs and standard IST for pediatric patients with newly diagnosed SAA. In mesenchymal stem cells (MSC) group, UC-MSCs were injected intravenously at a dose of 1 × 106/kg per week starting on the 14th day after administration of rabbit antithymocyte globulin (ATG), for a total of 3 weeks. The clinical outcomes and adverse events of patients with UC-MSCs infusion were assessed when compared with a concurrent control group in which patients received standard IST alone. RESULTS: Nine patients with a median age of 4 years were enrolled as the group with MSC, while the data of another 9 childhood SAA were analysed as the controls. Four (44%) patients in MSC group developed anaphylactic reactions which were associated with rabbit ATG. When compared with the controls, neither the improvement of blood cell counts, nor the change of T-lymphocytes after IST reached statistical significance in MSC group (both p > 0.05) and there were one (11%) patient in MSC group and two (22%) patients in the controls achieved partial response (PR) at 90 days after IST. After a median follow-up of 48 months, there was no clone evolution occurring in both groups. The 4-year estimated overall survival (OS) rate in two groups were both 88.9% ± 10.5%, while the 4-year estimated failure-free survival (FFS) rate in MSC group was lower than that in the controls (38.1% ± 17.2% vs. 66.7% ± 15.7%, p = 0.153). CONCLUSIONS: Concomitant use of IST and UC-MSCs in SAA children is safe but may not necessarily improve the early response rate and long-term outcomes. This clinical trial was registered at ClinicalTrials.gov, identifier: NCT02218437 (registered October 2013).
Asunto(s)
Anemia Aplásica , Células Madre Mesenquimatosas , Anemia Aplásica/terapia , Niño , Ciclosporina , Humanos , Estudios Prospectivos , Resultado del Tratamiento , Cordón UmbilicalRESUMEN
AIMS: To investigate the characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019 (COVID-19). METHODS AND RESULTS: We enrolled 671 eligible hospitalized patients with severe COVID-19 from 1 January to 23 February 2020, with a median age of 63 years. Clinical, laboratory, and treatment data were collected and compared between patients who died and survivors. Risk factors of death and myocardial injury were analysed using multivariable regression models. A total of 62 patients (9.2%) died, who more often had myocardial injury (75.8% vs. 9.7%; P < 0.001) than survivors. The area under the receiver operating characteristic curve of initial cardiac troponin I (cTnI) for predicting in-hospital mortality was 0.92 [95% confidence interval (CI), 0.87-0.96; sensitivity, 0.86; specificity, 0.86; P < 0.001]. The single cut-off point and high level of cTnI predicted risk of in-hospital death, hazard ratio (HR) was 4.56 (95% CI, 1.28-16.28; P = 0.019) and 1.25 (95% CI, 1.07-1.46; P = 0.004), respectively. In multivariable logistic regression, senior age, comorbidities (e.g. hypertension, coronary heart disease, chronic renal failure, and chronic obstructive pulmonary disease), and high level of C-reactive protein were predictors of myocardial injury. CONCLUSION: The risk of in-hospital death among patients with severe COVID-19 can be predicted by markers of myocardial injury, and was significantly associated with senior age, inflammatory response, and cardiovascular comorbidities.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/mortalidad , Cardiopatías/virología , Neumonía Viral/complicaciones , Neumonía Viral/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , COVID-19 , China/epidemiología , Infecciones por Coronavirus/diagnóstico , Femenino , Estudios de Seguimiento , Cardiopatías/sangre , Cardiopatías/diagnóstico , Cardiopatías/mortalidad , Mortalidad Hospitalaria , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2 , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To compare the efficacy of the CAMS-2005 and CAMS-2009 regimens in treating children with non-core binding factor acute myeloid leukemia (non-CBF AML) and to study the prognosis factors. METHODS: A total of 161 children who were initially diagnosed with non-CBF AML from April 2005 to December 2015 were enrolled as study subjects, and were divided into a CAMS-2005 regimen group (n=52) and a CAMS-2009 regimen group (n=109) according to the chemotherapy regimen provided. The efficacy was retrospectively compared between the two groups. RESULTS: The complete remission (CR) rate at the first course of treatment was higher in the CAMS-2009 regimen group than that in the CMAS-2005 regimen group (63.3% vs 46.2%; P<0.05). There were no significant differences between the two groups in treatment-related mortality rate (11.9% vs 17.3%), recurrence rate (27.5% vs 28.8%), and three-year overall survival (OS) rate (44%±5% vs 28%±6%) (P>0.05). Children who achieved CR at the first course of treatment had significantly higher OS and event-free survival rates than those who did not achieved CR (P<0.01). CONCLUSIONS: The CAMS-2009 regimen is superior to the CAMS-2005 regimen in improving the CR rate in children with non-CBF AML after induction treatment. Whether CR is achieved at the first course of treatment can affect the OS rate of children with non-CBF AML.
Asunto(s)
Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica , Niño , Humanos , Pronóstico , Inducción de Remisión , Estudios RetrospectivosRESUMEN
Adenosine 2A receptor (A2A R) exerts protective roles in endotoxin- and/or ischemia-induced tissue damage. However, the role for A2A R in nonalcoholic fatty liver disease (NAFLD) remains largely unknown. We sought to examine the effects of global and/or myeloid cell-specific A2A R disruption on the aspects of obesity-associated NAFLD and to elucidate the underlying mechanisms. Global and/or myeloid cell-specific A2A R-disrupted mice and control mice were fed a high-fat diet (HFD) to induce NAFLD. In addition, bone marrow-derived macrophages and primary mouse hepatocytes were examined for inflammatory and metabolic responses. Upon feeding an HFD, both global A2A R-disrupted mice and myeloid cell-specific A2A R-defcient mice revealed increased severity of HFD-induced hepatic steatosis and inflammation compared with their respective control mice. In in vitro experiments, A2A R-deficient macrophages exhibited increased proinflammatory responses, and enhanced fat deposition of wild-type primary hepatocytes in macrophage-hepatocyte cocultures. In primary hepatocytes, A2A R deficiency increased the proinflammatory responses and enhanced the effect of palmitate on stimulating fat deposition. Moreover, A2A R deficiency significantly increased the abundance of sterol regulatory element-binding protein 1c (SREBP1c) in livers of fasted mice and in hepatocytes upon nutrient deprivation. In the absence of A2A R, SREBP1c transcription activity was significantly increased in mouse hepatocytes. CONCLUSION: Taken together, our results demonstrate that disruption of A2A R in both macrophage and hepatocytes accounts for increased severity of NAFLD, likely through increasing inflammation and through elevating lipogenic events due to stimulation of SREBP1c expression and transcription activity. (Hepatology 2018;68:48-61).
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptor de Adenosina A2A/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Animales , Células Cultivadas , Dieta Alta en Grasa/efectos adversos , Progresión de la Enfermedad , Femenino , Hepatocitos/metabolismo , Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Células Mieloides/metabolismoRESUMEN
OBJECTIVE: To study the clinical features of Wiskott-Aldrich syndrome (WAS) in children. METHODS: A retrospective analysis was performed for the clinical data of 13 children with WAS. RESULTS: All 13 children were boys, with a median age of onset of 3 months (range 1-48 months) and a median age of 24 months (range 1-60 months) at the time of diagnosis. Of the 13 children, only 3 had typical WAS and the remaining 10 children had X-linked thrombocytopenia (XLT). The mean WAS score was 2 (range 1-3), the mean platelet count was 20.5×109/L [range (13-46)×109/L], and the mean platelet volume was 8.1 fl (range 6.7-12.1 fl). Lymphocyte subsets and immunoglobulins were measured for 4 children, among whom 1 (25%) had a reduction in both the percentage of CD3+T cells per lymphocyte and lymphocyte per nuclear cells, 1(25%) had a reduction in CD3-CD56+ NK cells. Among these 4 children, 1 (25%) had an increase in IgG, 2 (50%) had a reduction in IgM, 1 (25%) had a reduction in IgA, and 4 (100%) had an increase in IgE. A total of 14 gene mutations belonging to 13 types were found in 13 children, among which there were 9 missense mutations (65%), 2 splicing mutations (14%), 2 nonsense mutation (14%), and 1 frameshift mutation (7%). The median follow-up time was 39 months (range 3-62 months), and all 13 children survived. CONCLUSIONS: Children with WAS often have a young age of onset, and most of them are boys. Major clinical features include thrombocytopenia with a reduction in platelet volume. Missense mutation is the main type of gene mutation.
Asunto(s)
Trombocitopenia , Síndrome de Wiskott-Aldrich , Preescolar , Humanos , Lactante , Masculino , Mutación , Estudios Retrospectivos , Proteína del Síndrome de Wiskott-AldrichRESUMEN
Idiopathic pulmonary fibrosis is an agnogenic chronic disorder with high morbidity and low survival rate. Quercetin is a flavonoid found in a variety of herbs with anti-fibrosis function. In this study, bleomycin was employed to induce a pulmonary fibrosis mouse model. The quercetin administration ameliorated bleomycin-induced pulmonary fibrosis, evidenced by the expression level changes of hydroxyproline, fibronectin, α-smooth muscle actin, Collagen I, and Collagen III. Similar results were observed in transforming growth factor (TGF)-ß-treated human embryonic lung fibroblast (HELF). The bleomycin or TGF-ß administration caused the increase of sphingosine-1-phosphate (S1P) level in pulmonary tissue and HELF cells, as well as its activation-required kinase, sphingosine kinase 1 (SphK1), and its degradation enzyme, sphinogosine-1-phosphate lyase (S1PL). However, the increase of S1P, SphK1, and S1PL was attenuated by application of quercetin. In addition, the effect of quercetin on fibrosis was abolished by the ectopic expression of SphK1. The colocalization of SphK1/S1PL and fibroblast specific protein 1 (FSP1) suggested the roles of fibroblasts in pulmonary fibrosis. In summary, we demonstrated that quercetin ameliorated pulmonary fibrosis in vivo and in vitro by inhibiting SphK1/S1P signaling.
Asunto(s)
Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Lisofosfolípidos/antagonistas & inhibidores , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Quercetina/farmacología , Transducción de Señal/efectos de los fármacos , Esfingosina/análogos & derivados , Animales , Células Cultivadas , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Lisofosfolípidos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Esfingosina/antagonistas & inhibidores , Esfingosina/metabolismoRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a rare chronic myeloid leukemia in children and has the features of both myelodysplastic syndrome and myeloproliferative neoplasm. It is highly malignant and has a poor treatment outcome. Children with JMML have a poor response to conventional chemotherapy. At present, hematopoietic stem cell transplantation is the only possible cure for this disease. In recent years, significant progress has been made in targeted therapy for mutant genes in the Ras signaling pathway and demethylation treatment of aberrant methylation of polygenic CpG islands. This article reviews the treatment and efficacy evaluation of JMML.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mielomonocítica Juvenil , Síndromes Mielodisplásicos , Niño , Humanos , Metilación , Transducción de SeñalRESUMEN
Metformin (MET), an anti-diabetic oral drug with antioxidant properties, has been proved to provide cardioprotective effects in patients with diabetic disease. However, the mechanism is unclear. This study aimd to investigate the effects of MET on the expressions of receptor for advanced glycation end products (RAGE) and high mobility group box 1 protein (HMGB1) in hyperglycemia-treated neonatal rat ventricular myocytes. Cardiocytes were prepared and cultured with high glucose and different concentrations of MET. The expressions of RAGE and HMGB1 were evaluated by Western blot analysis. The superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), lactate dehydrogenase (LDH) and creatine kinase (CK) were measured. After 12 h-incubation, MET significantly inhibited the increase of MDA, TNF-α, LDH and CK levels induced by high glucose, especially at the 5 × 10(-5) to 10(-4 )mol/L concentrations while inhibiting the decrease of SOD level. Meanwhile, RAGE and HMGB1 expression were significantly increased induced by hyperglycaemia for 24 h (P < 0.05). MET inhibited the expressions of RAGE and HMGB1 in a dose-dependent manner, especially at the 5 × 10(-5) to 10(-4 )mol/L concentrations (P < 0.05). In conclusion, our study suggested that MET could reduce hyperglycemia-induced cardiocytes injury by inhibiting the expressions of RAGE and HMGB1.
Asunto(s)
Proteína HMGB1/biosíntesis , Metformina/administración & dosificación , Miocitos Cardíacos/efectos de los fármacos , Receptores Inmunológicos/biosíntesis , Animales , Antioxidantes/metabolismo , Creatina Quinasa/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Productos Finales de Glicación Avanzada , Proteína HMGB1/genética , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/patología , L-Lactato Deshidrogenasa/metabolismo , Malondialdehído/metabolismo , Miocitos Cardíacos/patología , Ratas , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/genética , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Background: This study aims to elucidate the role of mitochondrial autophagy in metabolic dysfunction-associated steatohepatitis (MASH) by identifying and validating key mitophagy-related genes and diagnostic models with diagnostic potential. Methods: The gene expression profiles and clinical information of MASH patients and healthy controls were obtained from the Gene Expression Omnibus database (GEO). Limma and functional enrichment analysis were used to identify the mitophagy-related differentially expressed genes (mito-DEGs) in MASH patients. Machine learning models were used to select key mito-DEGs and evaluate their efficacy in the early diagnosis of MASH. The expression levels of the key mito-DEGs were validated using datasets and cell models. A nomogram was constructed to assess the risk of MASH progression based on the expression of the key mito-DEGs. The mitophagy-related molecular subtypes of MASH were evaluated. Results: Four mito-DEGs, namely MRAS, RAB7B, RETREG1, and TIGAR were identified. Among the machine learning models employed, the Support Vector Machine demonstrated the highest AUC value of 0.935, while the Light Gradient Boosting model exhibited the highest accuracy (0.9189), kappa (0.7204), and F1-score (0.9508) values. Based on these models, MRAS, RAB7B, and RETREG1 were selected for further analysis. The logistic regression model based on these genes could accurately predict MASH diagnosis. The nomogram model based on these DEGs exhibited excellent prediction performance. The expression levels of the three mito-DEGs were validated in the independent datasets and cell models, and the results were found to be consistent with the findings obtained through bioinformatics analysis. Furthermore, our findings revealed significant differences in gene expression patterns, immune characteristics, biological functions, and enrichment pathways between the mitophagy-related molecular subtypes of MASH. Subtype-specific small-molecule drugs were identified using the CMap database. Conclusion: Our research provides novel insights into the role of mitophagy in MASH and uncovers novel targets for predictive and personalized MASH treatments.
RESUMEN
OBJECTIVE: Hepatic insulin resistance, which leads to increased hepatic gluconeogenesis, is a major contributor to fasting hyperglycemia in type 2 diabetes mellitus (T2DM). However, the mechanism of impaired insulin-dependent suppression of hepatic gluconeogenesis remains elusive. Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER), ï¬rstly described as a neuron-specific Notch ligand, has been recently identiï¬ed as a susceptibility gene for T2DM through genome-wide association studies. We herein investigated whether DNER regulates hepatic gluconeogenesis and whether this is mediated by enhanced insulin signaling. METHODS: The association between DNER, tribbles homolog 3 (TRB3) and Akt signaling was evaluated in C57BL/6J, ob/ob and db/db mice by western blot analysis. DNER loss-of-function and gain-of-function in hepatic gluconeogenesis were analyzed by western blot analysis, quantitative real-time PCR, glucose uptake and output assay in AML-12 cells and partially validated in primary mouse hepatocytes. Hepatic DNER knockdown mice were generated by tail vein injection of adenovirus to confirm the effects of DNER in vivo. The interaction between DNER and TRB3 was investigated by rescue experiments, cycloheximide chase analysis, co-immunoprecipitation and immunofluorescence. The potential insulin-stimulated phosphorylation sites of DNER were determined by co-immunoprecipitation, LC-MS/MS analysis and site-specific mutagenesis. RESULTS: Here we show that DNER enhanced hepatic insulin signaling in gluconeogenesis by inhibiting TRB3, an endogenous Akt inhibitor, through the ubiquitin-proteasome degradation pathway. In AML-12 hepatocytes, insulin-stimulated activation of Akt and suppression of gluconeogenesis are attenuated by DNER knockdown, but potentiated by DNER over-expression. In C57BL/6J mice, hepatic DNER knockdown is accompanied by impaired glucose and pyruvate tolerance. Furthermore, the in vitro effects of DNER knockdown or over-expression on both Akt activity and hepatic gluconeogenesis can be rescued by TRB3 knockdown or over-expression, respectively. In response to insulin stimulation, DNER interacted directly with insulin receptor and was phosphorylated at Tyr677. This site-specific phosphorylation is essential for DNER to upregulate Akt activity and then downregulate G6Pase and PEPCK expression, by interacting with TRB3 directly and inducing TRB3 proteasome-dependent degradation. CONCLUSIONS: Taken together, the crosstalk between insulin-Akt and DNER-TRB3 pathways represents a previously unrecognized mechanism by which insulin regulates hepatic gluconeogenesis.
Asunto(s)
Proteínas de Ciclo Celular , Gluconeogénesis , Insulina , Hígado , Ratones Endogámicos C57BL , Complejo de la Endopetidasa Proteasomal , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Diabetes Mellitus Tipo 2/metabolismo , Hepatocitos/metabolismo , Insulina/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a disorder characterized by the simultaneous presence of myeloproliferative and myelodysplastic features, primarily affecting infants and young children. Due to the heterogeneous genetic background among patients, the current clinical and laboratory prognostic features are insufficient for accurately predicting outcomes. Thus, there is a pressing need to identify novel prognostic indicators. Red cell distribution width (RDW) is a critical parameter reflecting the variability in erythrocyte size. Recent studies have emphasized that elevated RDW serves as a valuable predictive marker for unfavorable outcomes across various diseases. However, the prognostic role of RDW in JMML remains unclear. Patients with JMML from our single-center cohort between January 2008 and December 2019 were included. Overall, 77 patients were eligible. Multivariate Cox proportional hazard models showed that patients with red cell distribution width coefficient of variation (RDW-CV) >17.35% at diagnosis were susceptible to much worse overall survival rate (hazard ratio [HR] = 5.22, confidence interval [CI] = 1.50-18.21, P = .010). Besides, the combination of RDW elevation and protein phosphatase non-receptor type 11 (PTPN11) mutation was likely to predict a subgroup with the worst outcomes in our cohort. RDW is an independent prognostic variable in JMML subjects. RDW may be regarded as an inexpensive biomarker to predict the clinical outcome in patients with JMML.
RESUMEN
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Bilobalide (BB) is a sesquiterpene isolated from Ginkgo biloba, and its role in IPF is poorly understood. Mice were intratracheally instilled with 2.5 mg/kg bleomycin (BLM) to induce IPF and then treated with 2.5, 5, and 10 mg/kg BB daily for 21 days. Treatment with BB ameliorated pathological injury and fibrosis of lung tissues in BLM-induced mice. BB suppressed BLM-induced inflammatory response in mice as demonstrated by reduced inflammatory cells counts (leukocytes, neutrophils, macrophages, and lymphocytes) and pro-inflammatory factors (CCL2 and TNF-α), as well as increased CXCL10 levels in BALF. The expression of BLM-induced hydroxyproline, LDH, and pro-fibrotic mediators including fibronectin, collagen I, α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-ß1, matrix metalloproteinase (MMP)-2, and MMP-9 in lung tissue was inhibited by BB treatment, and the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression was increased. BB blocked the phosphorylation of JNK and NF-κB, and the nuclear translocation of NF-κB in the lung tissue of mice induced by BLM. Additionally, it abated the activation of NLRP3 inflammasome in lung tissue induced by BLM, which led to the downregulation of IL-18 and IL-1ß in BALF. Our present study suggested that BB might ameliorate BLM-induced pulmonary fibrosis by inhibiting the early inflammatory response, which is probably via the inhibition of the JNK/NF-κB/NLRP3 signal pathway. Thus, BB might serve as a therapeutic potential agent for pulmonary inflammation and fibrosis.
RESUMEN
Adipokines are biologically active factors secreted by adipose tissue that act on local and distant tissues through autocrine, paracrine, and endocrine mechanisms. However, adipokines are believed to be involved in an increased risk of atherosclerosis. Classical adipokines include leptin, adiponectin, and ceramide, while newly identified adipokines include visceral adipose tissue-derived serpin, omentin, and asprosin. New evidence suggests that adipokines can play an essential role in atherosclerosis progression and regression. Here, we summarize the complex roles of various adipokines in atherosclerosis lesions. Representative protective adipokines include adiponectin and neuregulin 4; deteriorating adipokines include leptin, resistin, thrombospondin-1, and C1q/tumor necrosis factor-related protein 5; and adipokines with dual protective and deteriorating effects include C1q/tumor necrosis factor-related protein 1 and C1q/tumor necrosis factor-related protein 3; and adipose tissue-derived bioactive materials include sphingosine-1-phosphate, ceramide, and adipose tissue-derived exosomes. However, the role of a newly discovered adipokine, asprosin, in atherosclerosis remains unclear. This article reviews progress in the research on the effects of adipokines in atherosclerosis and how they may be regulated to halt its progression.
RESUMEN
BACKGROUND: Fanconi anemia (FA) is a rare autosomal recessive, X-linked or autosomal dominant disease. Few large-scale FA investigations of rare disease cohorts have been conducted in China. METHODS: We enrolled 148 patients diagnosed with FA according to evidence from the clinical phenotype, family history, and a set of laboratory tests. Next, the clinical manifestations and correlation between the genotype and phenotype of FA pediatric cases were investigated. RESULTS: The most common FA subtype in our cohort was FA-A (51.4 %), followed by FA-D2 and FA-P. Finger (26 %) and skin (25 %) deformities were the most common malformations. Based on family history, blood system diseases (51 %) had the highest incidence rate, followed by digestive system tumours. A set of new or prognosis-related mutation sites was identified. For example, c.2941 T > G was a new most common missense mutation site for FANCA. FANCP gene mutation sites were mainly concentrated in exons 12/14/15. The mutations of FANCI/FANCD2 were mainly located at the α helix and ß corners of the protein complex. FA-A/D1 patients with splicing or deletion mutations showed more severe disease than those with missense mutations. Chromosome 1/3/7/8 abnormalities were closely linked to the progression of FA to leukemia. CONCLUSION: Our study investigated the clinical features and genotype/phenotype correlation of 148 Chinese pediatric FA patients, providing new insight into FA.
Asunto(s)
Anemia de Fanconi , Humanos , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Pueblos del Este de Asia , Enfermedades Raras , Genotipo , Fenotipo , MutaciónRESUMEN
Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myeloproliferative disease, and newly diagnosed patients frequently cannot tolerate hematopoietic stem cell transplantation (HSCT) at diagnosis due to their poor condition. This retrospective analysis aimed to explore the short-term effect of decitabine-dominant therapy on improving the condition of JMML patients before HSCT. The subjects were 10 JMML patients. All patients were treated with decitabine after low-dose chemotherapy with an interval of 4 weeks before bridging to HSCT. The median treatment course was 3 cycles, and the overall response rate (ORR) was 70.0% after one cycle and 71.4% after three cycles. White blood cell (WBC) and monocyte counts were significantly lower after treatment, and spleen volume was also lower, though not significantly lower. The 12 month progression-free survival rate (PFS) was 80.0 ± 12.6%. Decitabine-dominant therapy was beneficial for reducing tumor burden and improving clinical condition.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mielomonocítica Juvenil , Humanos , Niño , Leucemia Mielomonocítica Juvenil/diagnóstico , Estudios Retrospectivos , Decitabina , Supervivencia sin ProgresiónRESUMEN
Children with severe aplastic anemia (SAA) face heterogeneous prognoses after immunosuppressive therapy (IST). There are few models that can predict the long-term outcomes of IST for these patients. The objective of this paper is to develop a more effective prediction model for SAA prognosis based on clinical electronic medical records from 203 children with newly diagnosed SAA. In the early stage, a novel model for long-term outcomes of SAA patients with IST was developed using machine-learning techniques. Among the indicators related to long-term efficacy, white blood cell count, lymphocyte count, absolute reticulocyte count, lymphocyte ratio in bone-marrow smears, C-reactive protein, and the level of IL-6, IL-8 and vitamin B12 in the early stage are strongly correlated with long-term efficacy (P < .05). Taken together, we analyzed the long-term outcomes of rabbit anti-thymocyte globulin and cyclosporine therapy for children with SAA through machine-learning techniques, which may shorten the observation period of therapeutic effects and reduce treatment costs and time.
RESUMEN
Glucagon-like peptide-1 (GLP-1), a gut incretin hormone secreted from L cells, and a GLP-1 receptor agonist, exendin-4 (Ex-4) has been shown to be cardioprotective and could exert beneficial effects through its anti-inflammatory property. However, the mechanism remains unclear. The purpose of this study was to investigate whether Ex-4 could ameliorate myocardial cell injury by inhibiting high mobility group box 1 (HMGB1) expression under high glucose condition. Neonatal rat ventricular myocytes were prepared and then cultured with high glucose and different concentration of Ex-4. Lactate dehydrogenase (LDH), creatine kinase (CK), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. HMGB1 expression was assessed by western blotting. Ex-4 significantly inhibited the increase in LDH, CK, TNF-α, IL-1ß and MDA levels induced by high glucose, especially at the 1 and 10 nM concentrations as well as suppressed the decrease in SOD level. Meanwhile, HMGB1 expression was markedly increased after 12 h of hyperglycaemia (P < 0.05), which was significantly inhibited by Ex-4, especially at the 1 and 10 nM concentrations (P < 0.05). The present study suggested that Ex-4 could reduce high glucose-induced cardiocytes injury, which may be associated with the inhibition of HMGB1 expression.
Asunto(s)
Citoprotección/efectos de los fármacos , Proteína HMGB1/metabolismo , Hiperglucemia/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Péptidos/farmacología , Receptores de Glucagón/agonistas , Ponzoñas/farmacología , Animales , Creatina Quinasa/metabolismo , Exenatida , Receptor del Péptido 1 Similar al Glucagón , Hiperglucemia/enzimología , Interleucina-1beta/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Malondialdehído/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimología , Ratas , Ratas Sprague-Dawley , Receptores de Glucagón/metabolismo , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Ovulatory disorders are the most common clinical feature exhibited among obese women. Initiation of ovulation physiologically requires a surge of gonadotropin-releasing hormone (GnRH) released from GnRH neurons located in the hypothalamus. These GnRH neurons receive metabolic signals from circulation and vicinal neurons to regulate GnRH release. Leptin acts indirectly on GnRH via adjacent leptin receptor (LEPR)-expressing neurons such as proopiomelanocortin (POMC), neuropeptide Y (NPY)/agouti-related peptide (AgRP), and neuronal nitric oxide (NO) synthase (nNOS) neurons to affect GnRH neuronal activities. Additionally, hypothalamic inflammation also affects ovulation independent of obesity. Therefore, this review focuses on hypothalamic mechanisms that underlie the disturbance of hypothalamic-pituitary-ovarian (HPO) axis during obesity with an attempt to promote future studies and/or novel therapeutic strategies for ovulatory disorders in obesity.