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Besides being a marker of kidney disease severity, albuminuria exerts a toxic effect on renal proximal tubular epithelial cells (RPTECs). We evaluated whether an unfolded protein response (UPR) or DNA damage response (DDR) is elicited in RPTECs exposed to high albumin concentration. The deleterious outcomes of the above pathways, apoptosis, senescence, or epithelial-to-mesenchymal transition (EMT) were evaluated. Albumin caused reactive oxygen species (ROS) overproduction and protein modification, and a UPR assessed the level of crucial molecules involved in this pathway. ROS also induced a DDR evaluated by critical molecules involved in this pathway. Apoptosis ensued through the extrinsic pathway. Senescence also occurred, and the RPTECs acquired a senescence-associated secretory phenotype since they overproduced IL-1ß and TGF-ß1. The latter may contribute to the observed EMT. Agents against endoplasmic reticulum stress (ERS) only partially alleviated the above changes, while the inhibition of ROS upregulation prevented both UPR and DDR and all the subsequent harmful effects. Briefly, albumin overload causes cellular apoptosis, senescence, and EMT in RPTECs by triggering UPR and DDR. Promising anti-ERS factors are beneficial but cannot eliminate the albumin-induced deleterious effects because DDR also occurs. Factors that suppress ROS overproduction may be more effective since they could halt UPR and DDR.
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Túbulos Renales Proximales , Transducción de Señal , Albúminas/metabolismo , Albúminas/toxicidad , Línea Celular , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal , Túbulos Renales Proximales/metabolismo , Especies Reactivas de Oxígeno/metabolismo , HumanosRESUMEN
The interleukin-1 gene cluster encodes cytokines, which modulate mesangial cell proliferation and matrix expansion, both constituting central factors in the development and progression of immunoglobulin A nephropathy (IgAN). A candidate-gene study was performed to examine the association of polymorphisms of the interleukin-1 gene cluster with the risk of progressive IgAN. To gain deeper insights into the involvement of interleukin genes in IgAN, a meta-analysis of genetic association studies (GAS) that examine the association between interleukin variants and IgAN was conducted. Association study: The case-control study consisted of 121 unrelated Caucasians with sporadic, histologically diagnosed IgAN and of 246 age- and sex-matched healthy controls. Persistent proteinuria (>2 g/24 h) and/or impaired kidney function (serum creatinine > 1.5 mg/dL) defined progressive (n = 67) vs. non-progressive (n = 54) IgAN cases. Genotypes were assessed for two promoter-region single-nucleotide polymorphisms, C-899T (rs1800587) in IL1A and C-511T (rs16944) in IL1B, and for one penta-allelic variable-length tandem repeat polymorphism (VNTR 86 bp intron 2) in IL1RN. The association of these variants with the susceptibility of IgAN and the development of progressive IgAN (healthy status, IgAN, progressive IgAN) was tested using the generalized odds ratio (ORG) metric. Linkage disequilibrium and haplotype analysis were also performed. Meta-analysis: We included in the meta-analysis 15 studies investigating association between 14 interleukin variants harbored in eight different genes and IgAN. The ORG was used to evaluate the association between interleukin variants and IgAN using random effects models. The present case-control study revealed association of IL1B C-511T (rs16944) with the progression of IgAN (p = 0.041; ORG = 2.11 (1.09-4.07)). On haplotype analysis, significant results were derived for the haplotypes C-C-1 (p = 0.005; OR = 0.456 (0.261~0.797)) and C-T-2 (p = 0.003; OR = 4.208 (1.545-11.50)). Regarding association and meta-analysis results, variants in IL1B (rs1143627 and rs16944), IL1RN (rs928940, rs439154, and rs315951) and IL10 (rs1800871) were associated with IgAN based on either genotype or allele counts. Genetic variants and haplotypes in the IL1B, IL1RN, and IL10 genes might contribute to an increased risk for development and progression of IgAN.
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Glomerulonefritis por IGA , Humanos , Glomerulonefritis por IGA/genética , Glomerulonefritis por IGA/patología , Estudios de Casos y Controles , Interleucina-10/genética , Predisposición Genética a la Enfermedad , Genotipo , Interleucinas/genética , Polimorfismo de Nucleótido Simple , Interleucina-1/genética , Interleucina-1beta/genéticaRESUMEN
AIMS: Diagnosis of primary membranous nephropathy (PMN) is mainly based on immunofluorescence/immunohistochemistry findings. However, assessment of specific features on optical microscopy can help to estimate the severity of the disease, guide treatment and predict the response. The aim of this study was to identify, classify and grade the precise histological findings in PMN to predict renal function outcome and guide treatment. METHODS AND RESULTS: Histological parameters, including focal segmental sclerosis (FSGS), tubular atrophy (TA), interstitial fibrosis (IF) and vascular hyalinosis (VH), were re-evaluated in 752 patients with PMN. Their predictive value was estimated separately, and also in a combination score (FSTIV) graded from 0 to 4. Finally, the impact of histology was assessed in the response to immunosuppressive treatment. Mean age of patients was 53.3 (15-85) years and most presented with nephrotic syndrome. FSGS was present in 32% and VH in 51% of the patients, while TA and IF were graded as stage ≥1 in 52% and 51.4%, respectively. The follow-up period was 122.3 (112-376) months. FSGS, TA and IF and VH were associated with impaired renal function at diagnosis (P = 0.02, P < 0.0001, P = 0.001 and P = 0.02, respectively) and at the end of follow-up (P = 0.004, P < 0.0001, P < 0.0001 and P = 0.04, respectively). In multiple regression and binary logistic analysis, the presence of FSGS and degree of TA were the most significant parameters predicting renal function outcome, defined either by eGFR (end), FSGS (r = 0.6, P < 0.0001) and TA (r = 0.6, P < 0.0001), or by the endpoint of >50% eGFR reduction, FSGS (P = 0.001) and TA (P = 0.02). Also, patients presented with FSGS, IF, VH and/or with FSTIV > 1 could benefit from immunosuppression, regardless of clinical presentation. CONCLUSIONS: The presence and degree of four histological indices, FSGS, VH, TA and IF, assessed separately or in combination, and FSTIV score not only predict renal function outcome after long-term follow-up, but can also help in the choice of appropriate treatment. Decisions concerning immunosuppressive treatment can be guided by pathology regardless of clinical findings.
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Glomerulonefritis Membranosa , Enfermedades Renales/patología , Riñón/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/patología , Glomerulonefritis Membranosa/terapia , Histocitoquímica , Humanos , Inmunosupresores/uso terapéutico , Enfermedades Renales/diagnóstico , Enfermedades Renales/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVES: Ischemia-reperfusion (I-R) injury is the most common cause of acute kidney injury (AKI). Experimental studies have shown that indoleamine 2,3-dioxygenase 1 (IDO) and the purinergic receptor P2X7 contribute to kidney I-R injury. We evaluated whether there is an interplay between IDO and P2X7 in the pathogenesis of I-R injury. METHODS: Primary renal proximal tubular epithelial cells (RPTECs) were subjected to anoxia or reoxygenation with or without specific inhibitors. Cell imaging, colorimetric assays, and Western blotting were used. RESULTS: Cell imaging revealed that inhibition of IDO, or all the purinergic receptors with an ATPase, or specific inhibition of P2X7 rescued the cells from anoxia or reoxygenation-induced cell death. This was confirmed with LDH release assay, which also detected the ferroptotic nature of cell death due to reoxygenation. On the contrary, activated cleaved caspase 3 increased during anoxia, showing that apoptosis prevails. All the aforementioned treatments prevented caspase increase. Both anoxia and reoxygenation increased extracellular ATP, IDO, and P2X7 expression. IDO remained unaffected by the above-mentioned treatments. On the contrary, treatment with apyrase or inhibition of P2X7decreased extracellular ATP and P2X7 expression, which are also decreased by inhibition of IDO. The first indicates a positive feedback loop regarding P2X7 activation, expression and function, while the latter implies that IDO controls P2X7 expression. CONCLUSIONS: In RPRECs subjected to anoxia or reoxygenation, IDO is upregulated, increasing P2X7 and contributing to anoxia or reoxygenation-induced cell death. Clarifying the molecular mechanisms implicated in kidney I-R injury is of particular interest since it may lead to new therapeutic strategies against AKI.
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Lesión Renal Aguda , Daño por Reperfusión , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa , Apoptosis , Daño por Reperfusión/metabolismo , Lesión Renal Aguda/prevención & control , Células Epiteliales , Hipoxia , Adenosina Trifosfato/farmacologíaRESUMEN
Heart failure (HF) and chronic kidney disease (CKD) are associated with high mortality. In both disorders, impaired iron homeostasis, mostly in the form of a functional iron deficiency, is a frequent co-morbidity. In HF, functional iron deficiency and management by i.v. iron supplementation have been proven to affect both prognosis and functional capacity. In the same context, iron supplementation is routine for the adequate management of renal anemia in CKD. In numerous recent studies in HF and in CKD, sodium-glucose transporter 2 (SGLT2) inhibitor treatment has been proven to significantly reduce mortality. Furthermore, the same trials showed that these drugs alleviate iron deficiency and anemia. These effects of SGLT2 inhibitors may be due to an amelioration of inflammation with reduced interleukin-6 (IL-6) and to an enhancement of autophagy with increased sirtuin 1 (SIRT1), both associated with modified production of hepcidin and enhanced ferritinophagy. However, the exact pathogenic basis of the beneficial SGLT2 inhibitor action is not fully elucidated. Nevertheless, effects on iron homeostasis might be a potential explanatory mechanism for the powerful SGLT2 inhibitors' cardiovascular and renal outcome benefits. In addition, the interaction between iron supplementation and SGLT2 inhibitors and its potential impact on prognosis remains to be clarified by future studies. This review represents a significant effort to explore the complex relationships involved, seeking to elucidate the intricate mechanisms by which SGLT2 inhibitors influence iron homeostasis.
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Ischemia-reperfusion injury is the leading cause of acute kidney injury. Reactive oxygen species (ROS) production causes cell death or senescence. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to anoxia-reoxygenation, inhibition of the Krebs cycle at the level of malate dehydrogenase-2 (MDH-2) decreases hypoxia-inducible factor-1α and oxidative stress and protects from apoptotic or ferroptotic cell death. Inhibition of MDH-2 decreased reoxygenation-induced upregulation of p53 and p21, restored the levels of the proliferation marker Ki-67, and prevented the upregulation of the senescence marker beta-galactosidase and interleukin-1ß production. MDH-2 inhibition reduced the reoxygenation-induced upregulation of ATP, but the alterations of critical cell metabolism enzymes allowed enough ATP production to prevent cell energy collapse. Thus, inhibition of the Krebs cycle at the level of MDH-2 protects RPTECs from anoxia-reoxygenation-induced death or senescence. MDH-2 may be a promising pharmaceutical target against ischemia-reperfusion injury.
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Subunidad alfa del Factor 1 Inducible por Hipoxia , Malato Deshidrogenasa , Daño por Reperfusión , Humanos , Adenosina Trifosfato/metabolismo , Apoptosis , beta-Galactosidasa/metabolismo , Células Epiteliales/metabolismo , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Interleucina-1beta/metabolismo , Antígeno Ki-67/metabolismo , Malato Deshidrogenasa/antagonistas & inhibidores , Preparaciones Farmacéuticas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The present study evaluated indoleamine 2,3dioxygenase 1 (IDO) kinetics and how it affects cell survival during the two distinct phases of ischemiareperfusion (IR) injury. Primary renal proximal tubular epithelial cells (RPTECs) were cultured under anoxia or reoxygenation with or without the IDO inhibitor 1DLmethyltryptophan, the arylhydrocarbon receptor (AhR) inhibitor CH223191 or the ferroptosis inhibitor αtocopherol. Using cell imaging, colorimetric assays, PCR and western blotting, it was demonstrated that IDO was upregulated and induced apoptosis during anoxia. The related molecular pathway entails tryptophan degradation, general control nonderepressible2 kinase (GCN2K) activation, increased level of phosphorylated eukaryotic translation initiation factor 2α, activating transcription factor (ATF)4, ATF3, C/EBP homologous protein, phosphorylated p53, p53, Bax, death receptor5 and eventually activated cleaved caspase3. Reoxygenation also upregulated IDO, which, in this case, induced ferroptosis. The related molecular pathway encompasses kynurenine production, AhR activation, cytochrome p450 enzymes increase, reactive oxygen species generation and eventually ferroptosis. In conclusion, in RPTECs, both anoxia and reoxygenation upregulated IDO, which in turn induced GCN2Kmediated apoptosis and AhRmediated ferroptosis. Since both phases of IR injury share IDO upregulation as a common point, its inhibition may prove a useful therapeutic strategy for preventing or attenuating IR injury.
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Hipoxia de la Célula , Células Epiteliales/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Túbulos Renales Proximales/citología , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 4/metabolismo , Animales , Apoptosis , Compuestos Azo/farmacología , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Células Epiteliales/efectos de los fármacos , Ferroptosis , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
A 69-year-old female living donor kidney transplant recipient presented with right facial painful edema. The patient's body mass index was 14 (kilograms per meter squared), and her creatinine clearance was 15 mL/min. A computed tomography detected a subcutaneous mass under the nasolabial fold in contact with the maxillary bone. A biopsy from an ipsilateral oral mucosal ulcer returned the diagnosis of Epstein-Barr virus-positive mucocutaneous ulcer. Within 2 weeks, the lesion perforated the tissue. The mass and the affected bone were removed, and histopathology detected inflammation with many microorganisms. The opportunistic pathogen Streptococcus anginosus was isolated from wound cultures. Immunosuppressives were restricted, antibiotics were administered, and the patient started hemodialysis. Rituximab was applied for the lymphoproliferative disease. The lesion healed, allowing for surgical restoration. Two years later, the patient has remained free of local pathology and with improved nutritional and functional status. Epstein-Barr virus-positive muco cutaneous ulcers should be considered in the differential diagnosis of oral and facial lesions of immunocompromised patients and may be complicated with bacterial infections.
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Infecciones por Virus de Epstein-Barr , Enfermedades Gastrointestinales , Trasplante de Riñón , Trastornos Linfoproliferativos , Infecciones Oportunistas , Úlceras Bucales , Anciano , Mejilla/patología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Femenino , Enfermedades Gastrointestinales/patología , Herpesvirus Humano 4 , Humanos , Hiperplasia/complicaciones , Hiperplasia/patología , Trasplante de Riñón/efectos adversos , Trastornos Linfoproliferativos/diagnóstico , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/tratamiento farmacológico , Úlceras Bucales/diagnóstico , Úlceras Bucales/tratamiento farmacológico , Úlceras Bucales/etiología , Resultado del Tratamiento , Úlcera/complicaciones , Úlcera/diagnóstico , Úlcera/tratamiento farmacológicoRESUMEN
BACKGROUND: Many lines of evidence highlight the genetic contribution on the development of diabetic nephropathy (DN). One of the studied genes is SERPINE1 whose the role in the risk of developing DN remains questionable. In order to elucidate the contribution of SERPINE1 in DN progression in the context of type 2 diabetes mellitus (T2DM), we conducted an association study and meta-analysis of SERPINE1 genetic variants. MATERIALS AND METHODS: A total of 190 patients with DN, 150 T2DM (type 2 diabetes mellitus) patients without DN and 238 healthy controls were recruited. We selected five tag single-nucleotide polymorphisms (SNPs) from the HapMap. The generalized odds ratio (ORG) was calculated to estimate the risk on DN development. Subgroup analyses based on ethnicity and type of diabetes were also performed. RESULTS: Both the present association study regarding SERPINE1 SNPs (rs2227667, rs2070682, rs1050813, rs2227690, rs2227692) did not found any significant association between SERPINE1 variants and DN and the meta-analysis of variant 4G>5G (rs1799889) did not also reveal a significant association between 4G>5G variant and DN in main and subgroup analyses. DISCUSSION: In conclusion, the present association study and meta-analysis provides strong evidence that SERPINE1 genetic variant 4G>5G is not implicated in the risk or development of DN in Caucasians. Further studies in other populations remain to further investigate the role of this variant in the course of DN.
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Nefropatías Diabéticas , Inhibidor 1 de Activador Plasminogénico , Polimorfismo de Nucleótido Simple , Anciano , Femenino , Humanos , Masculino , Alelos , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Oportunidad Relativa , Inhibidor 1 de Activador Plasminogénico/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Chronic antibody-mediated rejection remains a major cause of late graft loss. Regarding cellular alloimmunity, the immunosuppressive properties of indoleamine 2,3-dioxygenase (IDO) have been well investigated; however, little is known of its effects on humoral alloimmunity. Therefore, the present study aimed to evaluate the effects of IDO on humoral alloimmunity. We developed a method for the induction of humoral alloimmunity in a one-way mixed lymphocyte reaction (MLR), which was measured with an antibody-mediated complement-dependent cytotoxicity assay using resting cells, which are similar to the stimulator cells of the aforementioned MLR. In parallel, cellular alloimmunity was assessed in two-way MLRs. The IDO inhibitor 1-methyl-DL-tryptophan was used for evaluating the role of IDO. In order to investigate whether the pathways known to serve a role in the effects of IDO on T cells are applied in humoral alloimmunity, the general control nonderepressible-2 (GCN-2) kinase activator tryptophanol and the aryl hydrocarbon receptor (AhR) inhibitor CH223191 were employed. The IDO inhibitor was revealed to increased cellular autoimmunity, but was decreased by the GCN-2 kinase activator. Unexpectedly, the AhR inhibitor decreased cellular alloimmunity. In addition, the IDO inhibitor was observed to suppress humoral alloimmunity, which may occur in manners independent of GCN-2 kinase AhR. The present study proposed that IDO may decrease humoral alloimmunity in primary human peripheral blood mononuclear cells via pathways that differ to those associated with its effect on T cells.
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Along with infections, ultrafiltration failure due to the toxicity of glucose-containing peritoneal dialysis (PD) solutions is the Achilles' heel of PD method. Triggered by the protective effect of general control nonderepressible-2 (GCN-2) kinase activation against high-glucose conditions in other cell types, we evaluated whether the same occurs in human peritoneal mesothelial cells. We activated GCN-2 kinase with halofuginone or tryptophanol, and assessed the impact of this intervention on glucose transporter-1, glucose transporter-3, and sodium-glucose cotransporter-1, glucose influx, reactive oxygen species (ROS), and the events that result in glucotoxicity. These involve the inhibition of glyceraldehyde 3-phosphate dehydrogenase and the diversion of upstream glycolytic products to the aldose pathway (assessed by D-sorbitol), the lipid synthesis pathway (assessed by protein kinase C activity), the hexosamine pathway (determined by O-linked ß-N-acetyl glucosamine-modified proteins), and the advanced glycation end products generation pathway (assessed by methylglyoxal). Then, we examined the production of the profibrotic transforming growth factor-ß1 (TGF-ß1), the pro-inflammatory interleukin-8 (IL-8). Cell apoptosis was assessed by cleaved caspase-3, and mesothelial to mesenchymal transition (MMT) was evaluated by α-smooth muscle actin protein. High-glucose conditions increased glucose transporters, glucose influx, ROS, all the high-glucose-induced harmful pathways, TGF-ß1 and IL-8, cell apoptosis, and MMT. Halofuginone and tryptophanol inhibited all of the above high glucose-induced alterations, indicating that activation of GCN-2 kinase ameliorates glucotoxicity in human peritoneal mesothelial cells, preserves their integrity, and prevents MMT. Whether such a strategy could be applied in the clinic to avoid ultrafiltration failure in PD patients remains to be investigated.
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Soluciones para Diálisis/química , Glucosa/toxicidad , Peritoneo/citología , Proteínas Serina-Treonina Quinasas/metabolismo , Células Cultivadas , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Diálisis Peritoneal , Peritoneo/efectos de los fármacos , Peritoneo/metabolismo , Piperidinas/farmacología , Cultivo Primario de Células , Quinazolinonas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Triptófano/análogos & derivados , Triptófano/farmacologíaRESUMEN
INTRODUCTION: Management of the Primary Membranous Nephropathy (PMN) usually involves administration of immunosuppressives. Cyclophosphamide (Cyclo) and Calcineurin Inhibitors (CNIs) are both widely used but only limited data exist to compare their efficacy in long term follow-up. AIM: The aim of the present study was to estimate and compare long term effects of Cyclo and CNIs in patients with PMN. PATIENTS-METHODS: Clinical data, histologic findings and long term outcome were retrospectively studied. The response to treatment and rate of relapse was compared between patients treated with CNIs or Cyclo based immunosuppressive regimens. RESULTS: Twenty three centers participated in the study, with 752 PMN patients (Mean age 53.4(14-87) yrs, M/F 467/285), followed for 10.1±5.7 years. All patients were initially treated with Renin Angiotensin Aldosterone System inhibitors (RAASi) for at least 6 months. Based on their response and tolerance to initial treatment, patients were divided into 3 groups, group I with spontaneous remission, who had no further treatment, group II, continued on RAASi only, and group III on RAASi+immunosuppression. Immunosuppressive regimes were mainly based on CNIs or Cyclo. Frequent relapses and failure to treatment were more common between patients who had started on CNIs (n = 381) compared to those initially treated with Cyclo (n = 110), relapse rate: 25.2% vs. 6.4%, p<0.0001, and no response rate: 22.5% vs. 13.6%, p = 0.04, respectively. CONCLUSIONS: Long term follow up showed that administration of Cyclo in PMN is followed by better preservation of renal function, increased response rate and less frequent relapses, compared to CNIs.
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Inhibidores de la Calcineurina/uso terapéutico , Ciclofosfamida/uso terapéutico , Glomerulonefritis Membranosa/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Ischemia-reperfusion (I-R) injury causes several diseases, including acute kidney injury. Hibernating mammals survive periods of torpor with a marked drop in tissue perfusion, interspersed with periods of arousal, and consequently I-R injury. In the present study, sensitivity to anoxia and/or reoxygenation and alterations in cellular ATP and homeostasis of the two most energy consuming processes, protein translation and Na+-K+-ATPase function, were evaluated in renal proximal tubular epithelial cells of mouse or native hibernator hamster origin. Compared with the mouse cells, the hamster cells were less sensitive to anoxia and reoxygenation and ATP was preserved under anoxia. Anoxia triggered mechanisms that suppress protein translation in both species. However, under anoxia, the activity of ATPase, which is mostly attributed to Na+-K+-ATPase function, remained stable in the hamster cells but decreased in the mouse cells. In normoxia, ATPase activity in hamster cells was considerably lower than that in mouse cells. As the Na+-K+-ATPase pump preserves the ion gradient against passive leakage through ion channels, the lower energy demand for the function of this pump in hamster cells may indicate less ion leakage due to fewer ion channels. In accordance with this hypothesis, ouabain-treated hamster cells had a higher survival rate than mouse cells, indicating fewer ion channels and consequently slower deregulation of intracellular ion concentration and cell death due to Na+-K+-ATPase inhibition. Therefore, it is likely that the conserved energy from the suppression of protein translation is adequate enough to support the lower energy demand for Na+-K+-ATPase function and cell survival of hamster cells under anoxia. Clarifying how cells of a native hibernator manage energy under warm I-R may reveal novel and possible clinically applicable pathways for preventing I-R injury.
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BACKGROUND: Natural history, predisposing factors to an unfavourable outcome and the effect of various therapeutic regimens were evaluated in a cohort of 457 patients with immunoglobulin A nephropathy (IgAN) and follow-up of at least 12 months. METHODS: Patients with normal renal function and proteinuria <1 g/24 h as well as those with serum creatinine (SCr) >2.5 mg/dL and/or severe glomerulosclerosis received no treatment. Patients with normal or impaired renal function and proteinuria >1 g/24 h for >6 months received daily oral prednisolone or a 3-day course of intravenous (IV) methylprednisolone followed by oral prednisolone per os every other day or a combination of prednisolone and azathioprine. The clinical outcome was estimated using the primary endpoints of end-stage renal disease and/or doubling of baseline SCr. RESULTS: The overall 10-year renal survival was 90.8%, while end-stage renal disease and doubling of baseline SCr developed in 9.2% and 14.7% of patients, respectively. Risk factors related to the primary endpoints were elevated baseline SCr, arterial hypertension, persistent proteinuria >0.5 g/24 h and severity of tubulointerstial fibrosis. There was no difference in the clinical outcome of patients treated by the two regimens of corticosteroids; nevertheless, remission of proteinuria was more frequent in patients who received IV methylprednisolone (P = 0.000). The combination of prednisolone with azathioprine was not superior to IV methylprednisolone followed by oral prednisolone. Side effects related to immunossuppressive drugs were observed in 12.8% of patients. CONCLUSION: The clinical outcome of patients with IgAN was related to the severity of clinical and histological involvement. The addition of azathioprine to a corticosteroid-based regimen for IgAN does not improve renal outcome.
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The aim of this study was to construct control charts for the data that were obtained from the daily toxicological analysis of finished water (that is the water which has already been treated for human consumption) from the treated-water tanks of the Water Supply & Sewerage Corporation of Athens. The basic idea of the control charts is to test the hypothesis that there are only common causes of variability versus the alternative that there are special causes. The control charts are designed and evaluated under the assumption that the observations from the process are independent and identically distributed (iid) normally. However, the independence assumption is often violated in practice. Time or serial dependence (autocorrelation) may be present in many chemical procedures, and may have a significant effect on the properties of the control charts. The fact that a serious amount of autocorrelation was present in the data for the toxicity of the fished water had a serious impact on the typical control charts. The problem of the autocorrelation was overcome by the usage of a more sophisticated method based on time-series ARIMA models.
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Modelos Teóricos , Contaminantes del Agua/toxicidad , Abastecimiento de Agua , Aliivibrio fischeri/efectos de los fármacos , Aliivibrio fischeri/metabolismo , LuminiscenciaRESUMEN
PURPOSE: Disturbed iron homeostasis contributes to resistance to recombinant human erythropoietin (rHuEpo) in hemodialysis (HD) patients. Although increased hepcidin, which downregulates the iron exporter ferroportin, had been incriminated, such an association has not been confirmed. Albeit not universally accepted, it has been supported that in case of copper deficiency, decreased activity of multicopper oxidases induces endocytosis and degradation of ferroportin. Ferroportin in monocytes, serum copper, ceruloplasmin and markers of iron status were measured, and associations with rHuEpo resistance index (ERI) were evaluated. METHODS: After a 4-week washout period from iron treatment, 34 HD patients and 20 healthy volunteers enrolled in the study. Ferroportin was assessed by means of Western blotting, copper colorimetrically, whereas ceruloplasmin with enzyme-linked immunosorbent assay. Hemoglobin, serum iron, ferritin and transferrin saturation (TSAT) were also measured. RESULTS: Ferroportin in monocytes of HD patients was decreased. Serum copper, ceruloplasmin, iron and TSAT were decreased. No correlation between copper or ceruloplasmin and ferroportin was detected. ERI was negatively correlated with ferroportin and all the markers of iron adequacy, but not with copper or ceruloplasmin. CONCLUSION: Although copper deficiency and decreased ferroportin are common in HD patients, copper might not play role in ferroportin level in monocytes and in iron metabolism in this population.
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Proteínas de Transporte de Catión/análisis , Cobre/sangre , Monocitos/química , Diálisis Renal , Ceruloplasmina/análisis , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
In recent years microwave-assisted techniques (MATs) have been introduced as a new process design and operation for essential oils extraction, representing a viable alternative to conventional old-type methods of distillation which are routinely used for the isolation of essential oils from herbs, flowers and spices prior to gas chromatographic analysis. The novelty of the technique lies in a microwave heating source generating a mixture of boiling solvent with the raw plant material settled above (or drenched inside). Several variations of distillation techniques are evaluated in terms of substantial energy saving, rapidity, product yield, cleanliness and product quality. Results confirm the effectiveness of MATs, which allow extraction of essential oils in shorter extraction time (up-to 9 times faster), using "greener" procedures and provide a higher quality essential oil with better sensory and antioxidant properties.