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As the disease with high morbidity and mortality in the world, heart failure affects the development of human society. Due to its complicated pathology and limited treatment options, it is urgent to discover new disease targets and develop new treatment strategies. As innate immune cells accompanied by the evolution of heart failure, macrophages play an important role in cardiac homeostasis and stress. In recent years, the role of macrophages in the heart has attracted more and more attention as a potential target for heart failure intervention, and the research on cardiac macrophages has made important progress. Traditional Chinese medicine(TCM) has significant effects on regulating inflammatory response, treating heart failure, and maintaining homeostasis. In this article, researches on the functions of cardiac macrophages and application of TCM were reviewed from the source and classification of cardiac macrophages and the relationship of macrophages and cardiac inflammation, myocardial fibrosis, cardiac angiogenesis, and cardiac electrical conduction, which provided a basis for further basic research and clinical applications.
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Humanos , Medicina Tradicional China , Insuficiencia Cardíaca/tratamiento farmacológico , Macrófagos , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
In this study, untargeted metabolomics was conducted using the liquid chromatography-tandem mass spectrometry(LC-MS/MS) technique to analyze the potential biomarkers in the plasma of mice with heart failure with preserved ejection fraction(HFpEF) induced by a high-fat diet(HFD) and nitric oxide synthase inhibitor(Nω-nitro-L-arginine methyl ester hydrochloride, L-NAME) and explore the pharmacological effects and mechanism of Jiming Powder in improving HFpEF. Male C57BL/6N mice aged eight weeks were randomly assigned to a control group, a model group, an empagliflozin(10 mg·kg~(-1)·d~(-1)) group, and high-and low-dose Jiming Powder(14.3 and 7.15 g·kg~(-1)·d~(-1)) groups. Mice in the control group were fed on a low-fat diet, and mice in the model group and groups with drug intervention were fed on a high-fat diet. All mice had free access to water, with water in the model group and Jiming Powder groups being supplemented with L-NAME(0.5 g·L~(-1)). Drugs were administered on the first day of modeling, and 15 weeks later, blood pressure and cardiac function of the mice in each group were measured. Heart tissues were collected for hematoxylin-eosin(HE) staining to observe pathological changes and Masson's staining to observe myocardial collagen deposition. Untargeted metabolomics analysis was performed on the plasma collected from mice in each group, and metabolic pathway analysis was conducted using MetaboAnalyst 5.0. The results showed that the blood pressure was significantly lower and the myocardial concentric hypertrophy and left ventricular diastolic dysfunction were significantly improved in both the high-dose and low-dose Jiming Powder groups as compared with those in the model group. HE and Masson staining showed that both high-dose and low-dose Jiming Powder significantly alleviated myocardial fibrosis. In the metabolomics experiment, 23 potential biomarkers were identified and eight strongly correlated metabolic pathways were enriched, including linoleic acid metabolism, histidine metabolism, alpha-linolenic acid metabolism, glycerophospholipid metabolism, purine metabolism, porphyrin and chlorophyll metabolism, arachidonic acid metabolism, and pyrimidine metabolism. The study confirmed the pharmacological effects of Jiming Powder in lowering blood pressure and ameliorating HFpEF and revealed the mechanism of Jiming Powder using the metabolomics technique, providing experimental evidence for the clinical application of Jiming Powder in treating HFpEF and a new perspective for advancing and developing TCM therapy for HFpEF.
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Masculino , Ratones , Animales , Insuficiencia Cardíaca/metabolismo , Polvos , Volumen Sistólico/fisiología , Cromatografía Liquida , NG-Nitroarginina Metil Éster/uso terapéutico , Ratones Endogámicos C57BL , Espectrometría de Masas en Tándem , Metabolómica , Biomarcadores , AguaRESUMEN
Jiming Powder is a traditional ancient prescription with good therapeutic effect in the treatment of heart failure, but its mechanism lacks further exploration. In this study, a mouse model of coronary artery ligation was used to evaluate the effect and mechanism of Jiming Powder on myocardial fibrosis in mice with myocardial infarction. The study constructed a mouse model of heart failure after myocardial infarction using the method of left anterior descending coronary artery ligation. The efficacy of Jiming Powder was evaluated from multiple angles, including ultrasound imaging, hematoxylin-eosin(HE) staining, Masson staining, Sirius Red staining, and serum myocardial enzyme spectrum detection. Western blot analysis was performed to detect key proteins involved in ventricular remodeling, including transforming growth factor-β1(TGF-β1), α-smooth muscle actin(α-SMA), wingless-type MMTV integration site family member 3a(Wnt3a), β-catenin, matrix metallopeptidase 2(MMP2), matrix metallopeptidase 3(MMP3), TIMP metallopeptidase inhibitor 1(TIMP1), and TIMP metallopeptidase inhibitor 2(TIMP2). The results showed that compared with the model group, the high and low-dose Jiming Powder significantly reduced the left ventricular internal diameter in systole(LVID;s) and diastole(LVID;d), increased the left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS), effectively improved cardiac function in mice after myocardial infarction, and effectively reduced the levels of myocardial injury markers such as creatine kinase(CK), creatine kinase isoenzyme(CK-MB), and lactic dehydrogenase(LDH), thus protecting ischemic myocardium. HE staining showed that Jiming Powder could attenuate myocardial inflammatory cell infiltration after myocardial infarction. Masson and Sirius Red staining demonstrated that Jiming Powder effectively inhibited myocardial fibrosis, reduced the collagen Ⅰ/Ⅲ ratio in myocardial tissues, and improved collagen remodeling after myocardial infarction. Western blot results showed that Jiming Powder reduced the expression of TGF-β1, α-SMA, Wnt3a, and β-catenin, decreased the levels of MMP2, MMP3, and TIMP2, and increased the level of TIMP1, suggesting its role in inhibiting cardiac fibroblast transformation, reducing extracellular matrix metabolism in myocardial cells, and lowering collagen Ⅰ and α-SMA content, thus exerting an anti-myocardial fibrosis effect after myocardial infarction. This study revealed the role of Jiming Powder in improving ventricular remodeling and treating myocardial infarction, laying the foundation for further research on the pharmacological effect of Jiming Powder.
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Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , beta Catenina/metabolismo , Metaloproteinasa 3 de la Matriz/uso terapéutico , Polvos , Remodelación Ventricular , Volumen Sistólico , Función Ventricular Izquierda , Infarto del Miocardio/tratamiento farmacológico , Miocardio/patología , Insuficiencia Cardíaca/metabolismo , Colágeno/metabolismo , Creatina Quinasa , FibrosisRESUMEN
BACKGROUND: Gastric cancer (GC) is a malignant tumor originated from gastric mucosa epithelium. It is the third leading cause of cancer mortality in China. The early symptoms are not obvious. When it is discovered, it has developed to the advanced stage, and the prognosis is poor. In order to screen for potential genes for GC development, this study obtained GSE118916 and GSE109476 from the gene expression omnibus (GEO) database for bioinformatics analysis. METHODS: First, GEO2R was used to identify differentially expressed genes (DEG) and the functional annotation of DEGs was performed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The Search Tool for the Retrieval of Interacting Genes (STRING) tool was used to construct protein-protein interaction (PPI) network and the most important modules and hub genes were mined. Real time quantitative polymerase chain reaction assay was performed to verify the expression level of hub genes. RESULTS: A total of 139 DEGs were identified. The functional changes of DEGs are mainly concentrated in the cytoskeleton, extracellular matrix and collagen synthesis. Eleven genes were identified as core genes. Bioinformatics analysis shows that the core genes are mainly enriched in many processes related to cell adhesion and collagen. CONCLUSION: In summary, the DEGs and hub genes found in this study may be potential diagnostic and therapeutic targets.
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Neoplasias Gástricas , Biomarcadores de Tumor/metabolismo , Biología Computacional , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Pronóstico , Neoplasias Gástricas/genéticaRESUMEN
Dysregulation of glucose homeostasis contributes to insulin resistance and type 2 diabetes. Whilst exercise stimulated activation of AMP-activated protein kinase (AMPK), an important energy sensor, has been highlighted for its potential to promote insulin-stimulated glucose uptake, the underlying mechanisms for this remain largely unknown. Here we found that AMPK positively regulates the activation of Rab5, a small GTPase which is involved in regulating Glut4 translocation, in both myoblasts and skeletal muscles. We further verified that TBC1D17, identified as a potential interacting partner of Rab5 in our recent study, is a novel GTPase activating protein (GAP) of Rab5. TBC1D17-Rab5 axis regulates transport of Glut1, Glut4, and transferrin receptor. TBC1D17 interacts with Rab5 or AMPK via its TBC domain or N-terminal 1-306 region (N-Ter), respectively. Moreover, AMPK phosphorylates the Ser 168 residue of TBC1D17 which matches the predicted AMPK consensus motif. N-Ter of TBC1D17 acts as an inhibitory region by directly interacting with the TBC domain. Ser168 phosphorylation promotes intra-molecular interaction and therefore enhances the auto-inhibition of TBC1D17. Our findings reveal that TBC1D17 acts as a molecular bridge that links AMPK and Rab5 and delineate a previously unappreciated mechanism by which the activation of TBC/RabGAP is regulated.
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Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/genética , Proteínas Activadoras de GTPasa/metabolismo , Glucosa/metabolismo , Resistencia a la Insulina/genética , Proteínas de Unión al GTP rab5/metabolismo , Secuencia de Aminoácidos , Animales , Diabetes Mellitus Tipo 2/patología , Humanos , Masculino , Ratones , Fosforilación , TransfecciónRESUMEN
For more effective using of HHP (high hydrostatic pressure) in starch processing, in this study, molecular dynamics simulation was used to explore the effects of pressure on amylose molecular conformation at the atomic level. The results shown that, firstly, high pressure decreased the intramolecular hydrogen bonds and increased the amylose-solvent hydrogen bonds, which is consistent with the process of high pressure starch gelatinization. Secondly, high pressure made amylose polymers more "stout". Meanwhile, high pressure decreased the angle of α-1,4 glycosidic linkage and increased the dihedral angles of α-1,4 glycosidic linkage, which indicates that pressure has obvious effects on amylose molecular conformation. Thirdly, high pressure made amylose polymers more stable. Moreover, in view of the results of energies, HHP may have an opposite gelatinization mechanism to heating. The results may be complementary to the existing experimental phenomena and provide theoretical guidance value for the using of HHP in starch processing.
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Amilosa/química , Simulación de Dinámica Molecular , Enlace de Hidrógeno , Presión Hidrostática , Conformación Molecular , Solventes/químicaRESUMEN
Starch is an important resource in nature, and HHP (high hydrostatic pressure) is one of the most important physical modification technologies. In this study, molecular dynamics simulation was used to explore the interchain interaction and the changes of molecule conformations of amylopectin and double-amylose helix at atomic level in different pressure. The results shown that, firstly, high pressure increased the content of 4C1 chair conformation, decreased the RMSD (root mean square deviations) and RMSF (root mean square fluctuation), made molecules more stable. Secondly, high pressure increased the interchain VDW (Van der Waals) and electrostatic forces, then caused the decreases of the interchain distances and surface area of both amylopectin and double-amylose, made molecules more compact. Thirdly, high pressure decreased the intramolecular hydrogen bonds, increased the molecule-solvent hydrogen bonds. These findings can explain some existing experimental phenomena from the atomic level, meanwhile, it may also provide importance reference value for using of HHP in starch processing and the studies of starch granule structure.
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Amilopectina/química , Amilosa/química , Almidón/química , Presión Hidrostática , Conformación MolecularRESUMEN
Rab5 is a master regulator for endosome biogenesis and transport while its in vivo physiological function remains elusive. Here, we find that Rab5a is upregulated in several in vivo and in vitro myogenesis models. By generating myogenic Rab5a-deficient mice, we uncover the essential roles of Rab5a in regulating skeletal muscle regeneration. We further reveal that Rab5a promotes myoblast differentiation and directly interacts with insulin receptor substrate 1 (IRS1), an essential scaffold protein for propagating IGF signaling. Rab5a interacts with IRS1 in a GTP-dependent manner and this interaction is enhanced upon IGF-1 activation and myogenic differentiation. We subsequently identify that the arginine 207 and 222 of IRS1 and tyrosine 82, 89, and 90 of Rab5a are the critical amino acid residues for mediating the association. Mechanistically, Rab5a modulates IRS1 activation by coordinating the association between IRS1 and the IGF receptor (IGFR) and regulating the intracellular membrane targeting of IRS1. Both myogenesis-induced and IGF-evoked AKT-mTOR signaling are dependent on Rab5a. Myogenic deletion of Rab5a also reduces the activation of AKT-mTOR signaling during skeletal muscle regeneration. Taken together, our study uncovers the physiological function of Rab5a in regulating muscle regeneration and delineates the novel role of Rab5a as a critical switch controlling AKT-mTOR signaling by activating IRS1.
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Diferenciación Celular , Proteínas Sustrato del Receptor de Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Músculo Esquelético/fisiología , Mioblastos/citología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Regeneración/fisiología , Proteínas de Unión al GTP rab5/metabolismo , Animales , Línea Celular , Células HEK293 , Miembro Posterior/metabolismo , Humanos , Membranas Intracelulares/metabolismo , Ratones Endogámicos C57BL , Desarrollo de Músculos/genética , Mioblastos/metabolismo , Unión Proteica , ARN Interferente Pequeño/metabolismo , Receptor IGF Tipo 1/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Regulación hacia Arriba/genética , Proteínas de Unión al GTP rab5/genéticaRESUMEN
OBJECTIVE@#To investigate the clinical and immunological characteristics, treatment and prognosis of common variable immune deficiency (CVID) in adult patients.@*METHODS@#We retrospectively analyzed the clinical data of 13 adult patients hospitalized in our hospital for CVID diagnosed according to the criteria in International Consensus Document (2016), and analyzed their clinical manifestations, laboratory test results, imaging findings, pathological examinations and treatments.@*RESULTS@#The mean age of onset was 24.46±16.82 years in these patients, who had a mean age of 32.54±14.86 years at diagnosis with a median diagnostic delay of 5 years (IQR: 2-15 years). The main manifestation of the patients was repeated infections, including repeated respiratory tract infection (10 cases; 76.9%) and repeated diarrhea (3 cases; 23.1%). Three (23.1%) of the patients had autoimmune disease and 10 (76.9%) had chronic pulmonary disease. IgG, IgA and IgM were decreased in all the patients. The proportion of CD4+T cells decreased in 10 patients (76.9%), CD8+T cells increased in 11 patients (84.6%), and CD4/ CD8 decreased in 10 patients (76.9%). Complement C3 decreased in 58.3% (7/12) and C4 decreased in 33.3% (4/12) of the patients. Twelve patients (92.3%) were treated with intravenous infusion of gamma globulin with symptomatic treatments. One patient died due to massive gastrointestinal hemorrhage, and the other patients showed improve ments after the treatments and were discharged.@*CONCLUSIONS@#The clinical manifestations of CVID are diverse, and recurrent respiratory tract infection is the most common manifestation. Decreased IgG often accompanied by lowered IgA and IgM levels is a common finding in laboratory tests. The treatment of CVID currently relies on gamma globulin with symptomatic treatments for the complications.
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Adolescente , Adulto , Niño , Humanos , Persona de Mediana Edad , Adulto Joven , Enfermedades Autoinmunes , Inmunodeficiencia Variable Común , Diagnóstico Tardío , Inmunoglobulinas Intravenosas , Estudios RetrospectivosRESUMEN
The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. In this study, we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38 mitogen-activated protein kinase α (p38MAPKα) but not AKT1 rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts. Moreover, Hsp70 interacted with MK2, a substrate of p38MAPK, to regulate the stability of p38MAPK. Knockdown of Hsp70 also led to downregulation of both MK2 and p38MAPK in intact muscles and during cardiotoxin-induced muscle regeneration. Hsp70 bound MK2 to regulate MK2-p38MAPK interaction in myoblasts. We subsequently identified the essential regions required for Hsp70-MK2 interaction. Functional analyses showed that MK2 is essential for both myoblast differentiation and skeletal muscle regeneration. Taken together, our findings reveal a novel role of Hsp70 in regulating myoblast differentiation by interacting with MK2 to stabilize p38MAPK.
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Diferenciación Celular/fisiología , Proteínas HSP70 de Choque Térmico/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Regeneración/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Línea Celular , Regulación hacia Abajo/fisiología , Ratones , Ratones Endogámicos C57BL , Desarrollo de Músculos/fisiología , Músculo Esquelético/fisiología , Mioblastos/fisiología , Regulación hacia Arriba/fisiologíaAsunto(s)
Adenocarcinoma/patología , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/patología , Convulsiones/etiología , Adulto , Neoplasias Encefálicas/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Convulsiones/diagnóstico por imagen , Tomógrafos Computarizados por Rayos XRESUMEN
Objective To observe the effect of the decontamination bundle of care for prevention of nosocomial infection after cardiac surgery. Methods Patients who underwent routine perioperative care from January 2012 to December 2013 for cardiac surgery were enrolled as the control group, while patients with bundle of care from May 2014 to April 2016 as the decontamination group. The care bundle included preoperative nasopharyngeal screening for methicillin-resistant Staphylococcus aureus (MRSA), perioperative systematic decontamination, isolation and antibiotic prophylaxis (mupirocin and glycopeptide) for MRSA carriers. The clinical data and nosocomial infection was collected and statistically analyzed. Results There were 712 cases in the control group and the incidence of nosocomial infection was 8.29% (59/712) including 4 MRSA cases. The decontamination group enrolled 791 cases with 5.56% (44/791) nosocomial infection including 2 MRSA cases. The bundles of care inhibited the nosocomial infection significantly (χ2=4.356, P<0.05), and there was a trend of decrease on MRSA infection. A total of 6 cases (0.76%) in the decontamination group were detected as MRSA colonization, but none of them got infected. Conclusions The care bundle of perioperative decontamination is useful to prevent nosocomial infection in cardiac surgery, especially to MRSA infection.
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Objective To observe the effect of the decontamination bundle of care for prevention of nosocomial infection after cardiac surgery. Methods Patients who underwent routine perioperative care from January 2012 to December 2013 for cardiac surgery were enrolled as the control group, while patients with bundle of care from May 2014 to April 2016 as the decontamination group. The care bundle included preoperative nasopharyngeal screening for methicillin-resistant Staphylococcus aureus (MRSA), perioperative systematic decontamination, isolation and antibiotic prophylaxis (mupirocin and glycopeptide) for MRSA carriers. The clinical data and nosocomial infection was collected and statistically analyzed. Results There were 712 cases in the control group and the incidence of nosocomial infection was 8.29% (59/712) including 4 MRSA cases. The decontamination group enrolled 791 cases with 5.56% (44/791) nosocomial infection including 2 MRSA cases. The bundles of care inhibited the nosocomial infection significantly (χ2=4.356, P<0.05), and there was a trend of decrease on MRSA infection. A total of 6 cases (0.76%) in the decontamination group were detected as MRSA colonization, but none of them got infected. Conclusions The care bundle of perioperative decontamination is useful to prevent nosocomial infection in cardiac surgery, especially to MRSA infection.
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This study tried to use CD133 positive U251 glioblastoma stem cells to establish nude mice model of transplanted tumor. CD133 positive U251 stem cells were isolated and identified. Twenty-five male nude mice were divided into three groups: U251 cell group, U251 stem cell group and normal control group. U251 cells and stem cells were respectively inoculated into mouse brain to establish model of transplanted tumor. Mice growing condition and behavior were observed. Magnetic resonance imaging (MRI) was performed to detect tumor growth in brain. HE staining assay, immunohistochemical assay and CD34 marked microvascular density (MVD) test were performed. As a result, the successful rates of both model groups were 100%. Growing condition and behavior in U251 stem cell group was more significantly exaggerated and tumor growth and image in magnetic resonance in U251 stem cell group was more significantly malignant than that in U251 cell group. It could be found that models in U251 stem cell group showed stronger pathogolical malignance features than that in U251 cell group. Glial fibrillary acidic protein (GFAP) expression in U251 cell and stem cell group showed the transplanted tumor originated from astrocytes. CD34 in U251 stem cell group was highest and significantly higher than that in the other two groups. In conclusion, use of U251 stem cells to establish transplanted tumor model in nude mice is an excellent method and the model is more likely and malignant than the one established by cancer cells, which showed a new animal model to research glioma.
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Antígenos CD/metabolismo , Neoplasias Encefálicas/patología , Modelos Animales de Enfermedad , Glioblastoma/patología , Glicoproteínas/metabolismo , Ratones Desnudos , Péptidos/metabolismo , Trasplante de Células Madre , Antígeno AC133 , Animales , Antígenos CD34/metabolismo , Astrocitos/metabolismo , Astrocitos/patología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Separación Celular , Proteína Ácida Fibrilar de la Glía/metabolismo , Glioblastoma/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones , Trasplante de Neoplasias , Trasplante de Células Madre/métodosRESUMEN
Alkyl 2-cyano-3-methylthio-3-phosphonylacrylates were synthesized by the reaction of alkyl 2-cyano-3,3-dimethylthioacrylates with dialkyl phosphites. The structures of the new compounds were characterized by elemental analyses, IR, 1H-, 13C- and 31P-NMR spectral data. These compounds were tested in vitro against pathogenic fungi, namely, Fusarium graminearum, Cytospora mandshurica and Fusarium oxysporum. Amongst all compounds, 2d and 2t were found to be effective against the tested fungi at 50 microg/mL. A half-leaf method was used to determine the in vivo protective, inactivation and curative efficacies of the title products against tobacco mosaic virus (TMV). Title compounds 2a and 2b were found to possess good in vivo curative, protection and inactivation effects against TMV with inhibitory rates at 500 mg/L of 60.0, 89.4 and 56.5 and 64.2, 84.2 and 61.2 %, respectively. To the best of our knowledge, this is the first report on the antiviral and antifungal activity of alkyl 2-cyano-3-methylthio-3-phosphonylacrylates.
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Antifúngicos/síntesis química , Antifúngicos/farmacología , Antivirales/síntesis química , Antivirales/farmacología , Enbucrilato/síntesis química , Enbucrilato/farmacología , Fusarium/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Espectrofotometría Infrarroja , Virus del Mosaico del Tabaco/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the effects of losartan, a specific angiotensin II receptor blocker, on slowing progression of renal insufficiency in patients with biopsy-proven chronic allograft nephropathy (CAN) and the molecular mechanism of the therapy. METHODS: Twenty-two renal transplant recipients with biopsy-proven CAN (group A) were treated with losartan within two months after renal dysfunction for at least one year. Losartan was administered at a dose of 50 mg/d. Twenty-four recipients in the same fashion (group B) who never received angiotensin II receptor antagonist were studied as control. The investigation time for each patient lasted one year. Renal functions and concentrations of plasma and urine transforming growth factor-beta1 (TGF-beta1) were compared between the two groups at the initiation and end of the study. In group A, expressions of TGF-betal mRNA and immunofluorescence intensity of TGF-betal protein and pathological alterations in renal biopsy specimens were compared between before losartan therapy and after one year of the therapy. RESULTS: At the initiation of the investigation, no significant differences were found between group A and group B in clinical data such as donor age, cold-ischemia time, HLA mismatch, levels of creatinine clearance (Ccr), plasma and urine TGF-beta1 concentrations. One year later, 14 of 22 (63.6%) patients showed stable or improved graft functions in group A, and 4 of 24 (16.7%) in group B. The difference was significant (P < 0.05). At the end of the study, urine TGF-betal concentration was 273.8 +/- 84.1 pg/mg x Cr in group A and 457.2 +/- 78.9 pg/mg x Cr in group B. During one year study period, loss of Ccr was 6.6 +/- 5.4 mL/min in group A and 16.2 +/- 9.1 mL/min in group B. Both of the differences were significant between the two groups (P < 0.01). No significant differences were found in plasma TGF-betal concentrations between the four values determined at the initiation and end of the study in the two groups (F = 2.56, P > 0.05). After one year losartan therapy, group A showed a significant decrease in expressions of TGF-beta1 mRNA and TGF-betal protein in renal biopsy specimens [from 1.59 +/- 0.35 to 0.96 +/- 0.27 and from (10.83 +/- 2.33) x l0(6) to (6.41 +/- 1.53) x 10(6), respectively; both P < 0.01], but in light microscopy the histological changes were similar to the first renal biopsy. Losartan was excellently tolerated in all patients in group A. No cases with losartan therapy showed too low blood pressure and other side effects. CONCLUSION: This study suggests that losartan have an effect on slowing progression of CAN. Reducing production of intrarenal TGF-betal may play a decisive role in the efficacy of losartan.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Trasplante de Riñón , Losartán/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Factor de Crecimiento Transformador beta1/biosíntesis , Adolescente , Adulto , Anciano , Creatinina/sangre , Creatinina/orina , Progresión de la Enfermedad , Femenino , Humanos , Riñón/patología , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/metabolismo , Complicaciones Posoperatorias/patología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/cirugía , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
<p><b>OBJECTIVE</b>To investigate the effects of losartan, a specific angiotensin II receptor blocker, on slowing progression of renal insufficiency in patients with biopsy-proven chronic allograft nephropathy (CAN) and the molecular mechanism of the therapy.</p><p><b>METHODS</b>Twenty-two renal transplant recipients with biopsy-proven CAN (group A) were treated with losartan within two months after renal dysfunction for at least one year. Losartan was administered at a dose of 50 mg/d. Twenty-four recipients in the same fashion (group B) who never received angiotensin II receptor antagonist were studied as control. The investigation time for each patient lasted one year. Renal functions and concentrations of plasma and urine transforming growth factor-beta1 (TGF-beta1) were compared between the two groups at the initiation and end of the study. In group A, expressions of TGF-betal mRNA and immunofluorescence intensity of TGF-betal protein and pathological alterations in renal biopsy specimens were compared between before losartan therapy and after one year of the therapy.</p><p><b>RESULTS</b>At the initiation of the investigation, no significant differences were found between group A and group B in clinical data such as donor age, cold-ischemia time, HLA mismatch, levels of creatinine clearance (Ccr), plasma and urine TGF-beta1 concentrations. One year later, 14 of 22 (63.6%) patients showed stable or improved graft functions in group A, and 4 of 24 (16.7%) in group B. The difference was significant (P < 0.05). At the end of the study, urine TGF-betal concentration was 273.8 +/- 84.1 pg/mg x Cr in group A and 457.2 +/- 78.9 pg/mg x Cr in group B. During one year study period, loss of Ccr was 6.6 +/- 5.4 mL/min in group A and 16.2 +/- 9.1 mL/min in group B. Both of the differences were significant between the two groups (P < 0.01). No significant differences were found in plasma TGF-betal concentrations between the four values determined at the initiation and end of the study in the two groups (F = 2.56, P > 0.05). After one year losartan therapy, group A showed a significant decrease in expressions of TGF-beta1 mRNA and TGF-betal protein in renal biopsy specimens [from 1.59 +/- 0.35 to 0.96 +/- 0.27 and from (10.83 +/- 2.33) x l0(6) to (6.41 +/- 1.53) x 10(6), respectively; both P < 0.01], but in light microscopy the histological changes were similar to the first renal biopsy. Losartan was excellently tolerated in all patients in group A. No cases with losartan therapy showed too low blood pressure and other side effects.</p><p><b>CONCLUSION</b>This study suggests that losartan have an effect on slowing progression of CAN. Reducing production of intrarenal TGF-betal may play a decisive role in the efficacy of losartan.</p>
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Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Farmacología , Creatinina , Sangre , Orina , Progresión de la Enfermedad , Riñón , Patología , Trasplante de Riñón , Losartán , Farmacología , Complicaciones Posoperatorias , Metabolismo , Patología , ARN Mensajero , Genética , Insuficiencia Renal Crónica , Quimioterapia , Patología , Cirugía General , Factor de Crecimiento Transformador beta1 , GenéticaRESUMEN
OBJECTIVE: To determine the relation between transforming growth factor beta1 (TGF-beta1) in allograft and long-term renal function. METHODS: Urine TGF-beta1 relative concentration (divided by urine creatinine) was tested in 168 recipients whose renal function was normal between August 1, 2000 and March 31, 2001. Twenty patients with higher urine TGF-beta1 relative concentrations formed Group A, and another 20 patients with lower urine TGF-beta1 formed Group B. In both groups biopsies were carried out in 15 cases and 12 cases respectively, and TGF-beta1 in the biopsis was tested by immunofluorescence. Blood TGF-beta1 concentrations in the 2 groups were also tested. Three years later, the renal function was compared between the 2 groups. Biopsies were carried out in renal recipients whose creatinine was higher than that of the normal. RESULTS: Blood TGF-beta1 concentrations in the 2 groups were not different significantly; 3 years after the transplantation, there was more loss of renal function and more chronic allograft nephropathy (CAN) cases in Group A than in Group B. Expression of TGF-beta1 in the allografts was higher in Group A than in Group B. The differences in the 2 groups were significant. CONCLUSION: The findings suggest that the higher expression of TGF-beta1 in the allografts is associated with the lower long-term survival rate of kidney graft. The level of urine TGF-beta1 after the renal transplantation can predict the long-term renal function.