RESUMEN
Anderson-Fabry disease (AFD) is an X-linked multisystemic disorder with a heterogeneous phenotype, resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) and leading to globotriaosylceramide systemic accumulation. Lysosomal storage is not the unique player in organ failure and different mechanisms could drive tissue damage, including endoplasmic reticulum (ER) stress and its related signaling pathway's activation. We identified a new missense variant in the signal peptide of α-GLA gene, c.13 A/G, in a 55-year-old woman affected by chronic kidney disease, acroparesthesia, hypohidrosis, and deafness and exhibiting normal values of lysoGb3 and αGLA activity. The functional study of the new variant performed by its overexpression in HEK293T cells showed an increased protein expression of a key ER stress marker, GRP78, the pro-apoptotic BAX, the negative regulator of cell cycle p21, the pro-inflammatory cytokine, IL1ß, together with pNFkB, and the pro-fibrotic marker, N-cadherin. Transmission electron microscopy showed signs of ER injury and intra-lysosomal inclusions. The proband's PBMC exhibited higher expression of TGFß 1 and pNFkB compared to control. Our findings suggest that the new variant, although it did not affect enzymatic activity, could cause cellular damage by affecting ER homeostasis and promoting apoptosis, inflammation, and fibrosis. Further studies are needed to demonstrate the variant's contribution to cellular and tissue damage.
Asunto(s)
Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Mutación Missense , alfa-Galactosidasa , Humanos , Femenino , Estrés del Retículo Endoplásmico/genética , Persona de Mediana Edad , Células HEK293 , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismo , Señales de Clasificación de Proteína/genética , Enfermedad de Fabry/genética , Enfermedad de Fabry/metabolismo , Enfermedad de Fabry/patología , Transducción de Señal/genéticaRESUMEN
Chronic kidney disease (CKD) is a disorder that causes changes in both the structure and function of the kidneys, causing complications such as hypertension, edema, and oliguria. Renal fibrosis is also a common pathological feature of CKD. Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix (ECM) proteins. The proteinase domain consists of a zinc ion in the active site, which contributes to its stabilization with another zinc and three calcium structural ions. Many cellular processes are controlled by MMPs, such as cell-cell interactions and various signaling pathways, while they are also involved in degrading substrates on cell surfaces. Tissue inhibitors of metalloproteinases (TIMPs) are key regulators of metalloproteinases, and both are involved in regulating cell turnover, the regulation, and the progression of fibrosis and apoptosis in the tissue. MMPs play a role in renal fibrosis, such as the tubular cell epithelial-mesenchymal transition (TEM), activation of resident fibroblasts, endothelial-mesenchymal transition (EndoMT), and pericyte-myofibroblast transdifferentiation. This review aims to show the mechanisms through which MMPs contribute to renal fibrosis, paying particular attention to MMP-9 and the epithelial-mesenchymal transition.
Asunto(s)
Transición Epitelial-Mesenquimal , Fibrosis , Riñón , Metaloproteinasas de la Matriz , Humanos , Metaloproteinasas de la Matriz/metabolismo , Riñón/patología , Riñón/metabolismo , Animales , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/enzimología , Metaloproteinasa 9 de la Matriz/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/enzimología , Enfermedades Renales/etiologíaRESUMEN
Chronic kidney disease (CKD) induces several systemic effects, including the accumulation and production of uremic toxins responsible for the activation of various harmful processes. Gut dysbiosis has been widely described in CKD patients, even in the early stages of the disease. The abundant discharge of urea and other waste substances into the gut favors the selection of an altered intestinal microbiota in CKD patients. The prevalence of bacteria with fermentative activity leads to the release and accumulation in the gut and in the blood of several substances, such as p-Cresol (p-C), Indoxyl Sulfate (IS) and p-Cresyl Sulfate (p-CS). Since these metabolites are normally eliminated in the urine, they tend to accumulate in the blood of CKD patients proportionally to renal impairment. P-CS, IS and p-C play a fundamental role in the activation of various pro-tumorigenic processes, such as chronic systemic inflammation, the increase in the production of free radicals and immune dysfunction. An up to two-fold increase in the incidence of colon cancer development in CKD has been reported in several studies, although the pathogenic mechanisms explaining this compelling association have not yet been described. Based on our literature review, it appears likely the hypothesis of a role of p-C, IS and p-CS in colon cancer development and progression in CKD patients.
Asunto(s)
Neoplasias del Colon , Fallo Renal Crónico , Insuficiencia Renal Crónica , Humanos , Indicán , Tóxinas Urémicas , Sulfatos , Insuficiencia Renal Crónica/metabolismo , InflamaciónRESUMEN
Nod-like receptor protein 3 (NLRP3) is a multi-protein complex belonging to the innate immune system, whose activation by danger stimuli promotes inflammatory cell death. Evidence supports the crucial role of NLRP3 inflammasome activation in the transition of acute kidney injury to Chronic Kidney Disease (CKD), by promoting both inflammation and fibrotic processes. Variants of NLRP3 pathway-related genes, such as NLRP3 itself and CARD8, have been associated with susceptibility to different autoimmune and inflammatory diseases. In this study, we investigated for the first time the association of functional variants of NLRP3 pathway-related genes (NLRP3-rs10754558, CARD8-rs2043211), with a susceptibility to CKD. A cohort of kidney transplant recipients, dialysis and CKD stage 3-5 patients (303 cases) and a cohort of elderly controls (85 subjects) were genotyped for the variants of interest and compared by using logistic regression analyses. Our analysis showed a significantly higher G allele frequency of the NLRP3 variant (67.3%) and T allele of the CARD8 variant (70.8%) among cases, compared with the control sample (35.9 and 31.2%, respectively). Logistic regressions showed significant associations (p < 0.001) between NLRP3 and CARD8 variants and cases. Our results suggest that the NLRP3 rs10754558 and CARD8 rs2043211 variants could be associated with a susceptibility to CKD.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD , Proteína con Dominio Pirina 3 de la Familia NLR , Insuficiencia Renal Crónica , Anciano , Humanos , Proteínas Adaptadoras de Señalización CARD/genética , Predisposición Genética a la Enfermedad , Genotipo , Inflamasomas/genética , Proteínas de Neoplasias/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Polimorfismo de Nucleótido Simple , Diálisis Renal , Insuficiencia Renal Crónica/genéticaRESUMEN
Fabry Disease (FD) is a rare lysosomal storage disorder caused by mutations in the GLA gene on the X chromosome, leading to a deficiency in α-galactosidase A (AGAL) enzyme activity. This leads to the accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3), in vital organs such as the kidneys, heart, and nervous system. While FD was initially considered predominantly affecting males, recent studies have uncovered that heterozygous Fabry women, carrying a single mutated GLA gene, can manifest a wide array of clinical symptoms, challenging the notion of asymptomatic carriers. The mechanisms underlying the diverse clinical manifestations in females remain not fully understood due to X-chromosome inactivation (XCI). XCI also known as "lyonization", involves the random inactivation of one of the two X chromosomes. This process is considered a potential factor influencing phenotypic variation. This review delves into the complex landscape of FD in women, discussing its genetic basis, the available biomarkers, clinical manifestations, and the potential impact of XCI on disease severity. Additionally, it highlights the challenges faced by heterozygous Fabry women, both in terms of their disease burden and interactions with healthcare professionals. Current treatment options, including enzyme replacement therapy, are discussed, along with the need for healthcare providers to be well-informed about FD in women, ultimately contributing to improved patient care and quality of life.
Asunto(s)
Enfermedad de Fabry , Enfermedades por Almacenamiento Lisosomal , Masculino , Humanos , Femenino , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/genética , Calidad de Vida , Riñón , BiomarcadoresRESUMEN
The nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome, a multiprotein complex belonging to the innate immune system, plays a key role in the chronic inflammatory response, through the production of proinflammatory cytokines, IL-1ß and IL-18, which can elicit their effects through receptor activation, both locally and systemically. Furthermore, it has been demonstrated the interaction of NLRP3 inflammasome components with redox signaling, endoplasmic reticulum stress, and mitochondrial function. A growing literature reported the involvement of NLRP3 platform dysregulation in the pathophysiology of different chronic diseases so it has been proposed that the inhibition of NLRP3 inflammasome could represent a new potential therapeutic target in the management of autoimmune and chronic inflammatory diseases, including cancer. In addition, it has been demonstrated that Sars-CoV2 preferentially activates NLRP3 inflammasome, strongly contributing to the hyperinflammatory state responsible for COVID-19. Recently, in vitro and animal models of both infectious and non-infectious male genital tract diseases affecting fertility, demonstrated the activation of the innate immune system, leading to increased levels of pro-inflammatory cytokines, as well as apoptosis and pyroptosis and that it was likely mediated by activation of the NLRP3 inflammasome. The objective of this review was to analyze the evidence on the role and the mechanisms by which NLRP3-inflammasome pathway activation may exert detrimental effects on the male reproductive system. Furthermore, although the literature data are still discordant, this review also highlighted the possible connection between SARS-CoV-2 infection/NLRP3 activation/oxidative stress and male infertility.
RESUMEN
BACKGROUND: Fabry disease (FD) is a rare X-linked multisystem lysosomal storage disease caused by partial or total deficiency of a-galactosidase A (GLA). A progressive involvement of the kidneys, heart, and brain arteries has been reported. Using the transcranial color-coded duplex Doppler (TCCD), we report the case of a Fabry disease (FD) patient with a reduction in the cerebrovascular reactivity of the basilar artery (BA). METHODS: A 46-year-old male asymptomatic FD patient underwent ultrasound intracranial investigation. CASE PRESENTATION: We report the case of a 46-year-old man affected by asymptomatic FD, who presented to our observation for episodes of vertigo. Cerebral MRI and AngioMRI were found to be normal. There was no postural hypotension observed. Otolaryngology and cardiac examinations revealed no pathological condition. A TCCD showed normal cerebral vascular reactivity (CVR) in the bilateral middle cerebral arteries (MCA), breath-holding index (BHI) was 1.3 in the right MCA (RMCA) and 1.4 in left MCA (LMCA), and BHI in the basilar artery (BA) was reduced (BHI: 0,56). CONCLUSION: This case suggests an earlier alteration of CVR in the posterior cerebral circulation than in the anterior cerebral circulation in an asymptomatic FD patient. This alteration of CVR may be an earlier marker of FD diagnosis.
Asunto(s)
Enfermedad de Fabry , Masculino , Humanos , Persona de Mediana Edad , Enfermedad de Fabry/diagnóstico por imagen , Ultrasonografía Doppler Transcraneal , Circulación Cerebrovascular , Arteria Cerebral Media/diagnóstico por imagen , Arteria Basilar/diagnóstico por imagenRESUMEN
The mammalian target of rapamycin inhibitor (mTOR-I) Rapamycin, a drug widely used in kidney transplantation, exerts important anti-cancer effects, particularly in Kaposi's Sarcoma (KS), through several biological interactions. In this in vivo and in vitro study, we explored whether the activation of the autophagic pathway through the low-affinity receptor for nerve growth factor, p75NTR , may have a pivotal role in the anti-cancer effect exerted by Rapamycin in S. Our Kimmunohistochemistry results revealed a significant hyper-activation of the autophagic pathway in KS lesions. In vitro experiments on KS cell lines showed that Rapamycin exposure reduced cell viability by increasing the autophagic process, in the absence of apoptosis, through the transcriptional activation of p75NTR via EGR1. Interestingly, p75NTR gene silencing prevented the increase of the autophagic process and the reduction of cell viability. Moreover, p75NTR activation promoted the upregulation of phosphatase and tensin homolog (PTEN), a tumour suppressor that modulates the PI3K/Akt/mTOR pathway. In conclusion, our in vitro data demonstrated, for the first time, that in Kaposi's sarcoma, autophagy triggered by Rapamycin through p75NTR represented a major mechanism by which mTOR inhibitors may induce tumour regression. Additionally, it suggested that p75NTR protein analysis could be proposed as a new potential biomarker to predict response to Rapamycin in kidney transplant recipients affected by Kaposi's sarcoma.
Asunto(s)
Sarcoma de Kaposi , Sirolimus , Apoptosis , Autofagia , Humanos , Fosfatidilinositol 3-Quinasas , Sarcoma de Kaposi/patología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: The activation of NLRP3 inflammasome machinery has a central role in obesity-induced inflammation. Genetic studies well support the involvement of functional variants of NLRP3 and its negative regulator, CARD8, in the pathogenesis of complex diseases with an inflammatory background. We have investigated the influence of NLRP3 (rs4612666; rs10754558) and CARD8 (rs204321) genetic variants in both the inflammatory status of visceral adipose tissue (VAT) from patients with severe obesity and in the systemic oxidative stress before and after sleeve-gastrectomy (SLG). METHODS: Twenty-three consecutive severe obese patients candidate to SLG were enrolled in the study. Visceral adipose tissue (VAT) biopsies, obtained during SLG, were used to evaluate the expression of NLRP3, IL-1ß, IL-6, and MCP-1 by real-time RT-PCR. DNA was extracted from peripheral blood lymphocytes and genotyped by RFLP analysis. Before and 3 months after SLG, all patients underwent the assessment of oxidative stress, biochemical parameters, and body composition as measured by bioelectrical impedance analysis (BIA). RESULTS: Increased expression of NLRP3, IL-6, IL-1ß, and MCP-1 mRNA was observed in VAT of rs4612666 C variant carriers, in which higher oxidative stress was also detected as compared to non-carrier individuals. In all patients, oxidative stress, biochemical and BIA parameters improved after SLG, regardless of genotype. No significant correlations were found with the other genetic variants. CONCLUSIONS: Our results suggest that the NLRP3 rs4612666 C variant may promote a worse pro-inflammatory milieu and higher oxidative stress, thus leading patients to a more severe obesity phenotype. A larger study is needed to confirm this assumption and to investigate the impact of the NLRP3 rs4612666 C variant on severe obesity.
Asunto(s)
Grasa Intraabdominal , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas Adaptadoras de Señalización CARD/metabolismo , Humanos , Inflamasomas/genética , Grasa Intraabdominal/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas de Neoplasias/metabolismo , Obesidad/genética , Estrés Oxidativo/genéticaRESUMEN
Most of the common drugs used to treat the cervical cancer, which main etiological factor is the HPV infection, cause side effects and intrinsic/acquired resistance to chemotherapy. In this study we investigated whether an olive leaf extract (OLE), rich in polyphenols, was able to exert anti-tumor effects in human cervical cancer cells (HeLa). MTT assay results showed a reduction of HeLa cells viability OLE-induced, concomitantly with a gene and protein down-regulation of Cyclin-D1 and an up-regulation of p21, triggering intrinsic apoptosis. OLE reduced NFkB nuclear translocation, which constitutive activation, stimulated by HPV-oncoproteins, promotes cancer progression and functional studies revealed that OLE activated p21Cip/WAF1 in a transcriptional-dependent-manner, by reducing the nuclear recruitment of NFkB on its responsive elements. Furthermore, OLE treatment counteracted epithelial-to-mesenchymal-transition and inhibited anchorage-dependent and -independent cell growth EGF-induced. Finally, MTT assay results revealed that OLE plus Cisplatin strengthened the reduction of cells viability Cisplatin-induced, as OLE inhibited NFkB, AkT and MAPK pathways, all involved in Cisplatin chemoresistance. In conclusion, we demonstrated that in HeLa cells OLE exerts pro-apoptotic effects, elucidating the molecular mechanism and that OLE could mitigate Cisplatin chemoresistance. Further studies are needed to explore the potential coadiuvant use of OLE for cervical cancer treatment.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Olea/química , Extractos Vegetales/farmacología , Polifenoles/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Quinasas p21 Activadas/metabolismo , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Regulación hacia Arriba/efectos de los fármacos , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
INTRODUCTION: Cytomegalovirus (CMV) infection represents a common cause of morbidity and mortality in kidney transplant recipients (KTR). The NF-kB signaling pathway is highly involved in the pathogenesis of CMV infection. The -94ins/delATTG functional polymorphism in the promoter of NFKB1 has been associated with low intracellular levels of the protein and high incidence of inflammatory and autoimmune disease. In this study, we evaluated the association of this NFKB1 polymorphism with the risk of CMV infection. METHODS: CMV infection was defined as virus isolation or detection of viral antigens or nucleic acid in any body fluid or tissue specimen. Using Cox regression and survival analysis, we analyzed the association between the polymorphism and CMV infection as well as recurrence in the first 12 months after transplantation. RESULTS: We analyzed the -94ins/delATTG NFKB1 polymorphism of 189 KTRs. The 65% of CMV infections occurred in ins/ins group. Survival free from CMV infection was 54.7% for ins/ins group and 79.4% for deletion carriers one year after transplantation (P < 0.0001). At multivariate regression, deletion carriers showed a lower risk of CMV infection and recurrence with respect to ins/ins KTRs (HR = 0.224 P = 0.0002; HR = 0.307, P = 0.012, respectively). CONCLUSIONS: In conclusion, pretransplantation screening for NFKB1 -94ins/delATTG polymorphism may predict CMV infection and improve the management of patients at higher risk of infection in the post-transplant period.
Asunto(s)
Infecciones por Citomegalovirus/diagnóstico , Trasplante de Riñón/efectos adversos , Subunidad p50 de NF-kappa B/genética , Complicaciones Posoperatorias/diagnóstico , Regiones Promotoras Genéticas/genética , Adulto , Biomarcadores/análisis , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/virología , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Mutación INDEL , Incidencia , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/genética , Complicaciones Posoperatorias/virología , Valor Predictivo de las Pruebas , Cuidados Preoperatorios/métodos , PronósticoRESUMEN
BACKGROUND: Clinical studies have demonstrated that, after renal transplantation (TX), testosterone deficiency (TD) at the time of the procedure is independently associated with lower survival of the patient and graft. However, data between TD and the functional CAG polymorphism of the androgen receptor promoter (AR) are discordant. We investigated the prevalence of TD and its association with body composition, biochemical parameters, the Aging Males' Symptoms rating scale (AMS) domains and AR polymorphism. METHODS: In 112 TX patients, we assessed the AMS, biochemical/hormonal (FSH/LH/TT) anthropometric/bioimpedance analysis parameters, and AR CAG polymorphism of AR by gene sequencing. RESULTS: Median values of total testosterone (TT) were 340 ng/dl and 52% of TX patients were affected by TD. Significant correlations between TT and FSH and FSH and LH (p = 0.005, p < 0.0001, respectively) were found. TD patients had lower estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) (p = 0.034, p = 0.022 respectively) and showed higher values of C-reactive protein (p = 0.023) and fat tissue index/adipose tissue mass (p = 0.034 and p = 0.021, respectively), and lower values of serum albumin (p = 0.003) and high-density lipoprotein-cholesterol (p = 0.038) levels. Significant differences were found in the number of patients on mammalian target of rapamycin inhibitors immunosuppressant therapy (p = 0.045). Logistic regression analysis did not show any correlation between age, AMS scores, TT or CAG repeat length, gonadotropins, time of the transplant, and dialysis. CONCLUSIONS: Our results suggest that in TX recipients an appropriate sexual hormonal evaluation should be performed, as we found a high prevalence of TD. However, further studies are needed to clarify the association between TD and patient and graft survival.
Asunto(s)
Composición Corporal , Hipogonadismo/sangre , Trasplante de Riñón , Insuficiencia Renal Crónica/cirugía , Testosterona/deficiencia , Receptores de Trasplantes , Adulto , Anciano , Biomarcadores/sangre , Hormona Folículo Estimulante/sangre , Humanos , Hipogonadismo/epidemiología , Hipogonadismo/genética , Hipogonadismo/fisiopatología , Italia/epidemiología , Trasplante de Riñón/efectos adversos , Hormona Luteinizante/sangre , Persona de Mediana Edad , Polimorfismo Genético , Prevalencia , Receptores Androgénicos/genética , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo , Testosterona/sangre , Resultado del TratamientoRESUMEN
Kidney cystic diseases are inherited disorders causing chronic renal failure. According to the genetic defect they are classified as diseases of the primary ciliary complex and uromodulin-associated diseases. Mutations in genes coding for ciliary proteins are the basis of a broad category of genetic diseases, called ciliopathies. To date, three important ciliopathies are known: the autosomal dominant form and the recessive shape of the polycystic kidney and the nephronophthisis (NPHP). Juvenile Nephronophthisis (NPHP) is a progressive renal tubulo-interstitial disorder with a form of autosomal recessive inheritance that progresses inexorably towards terminal renal failure. Three different forms have been distinguished: juvenile (NPH1), infantile (NPH2) and adolescent (NPH3). Juvenile Nephronophthisis or nephronophthisis type 1 (NPH1), is the most frequent form. In most patients with a suspected diagnosis of NPHP, based primarily on clinical and radiological data, the deletion in homozygous NPHP1 is present in 20-40% of cases. Heterozygous deletions are found in 6% of patients, with concomitant mutation of the NPHP1 gene on the second allele. In this study we subjected to genetic screening 6 patients with suspected NPHP causing chronic renal failure, belonging to 6 families. The genetic screening identified in 2/6 patients a deletion of exons 5-7-20 and in 4/6 patients an heterozygous deletion of exon 20 and an heterozygous deletion on exon 17 not yet described in literature. Our results suggest that genetic screening should be included in the diagnostic procedure of patients with suspected nephronophthisis and that it may be used alternatively to renal biopsy.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedades Renales Quísticas/congénito , Proteínas de la Membrana/genética , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Adolescente , Niño , Proteínas del Citoesqueleto , Exones/genética , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Enfermedades Renales Quísticas/complicaciones , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/cirugía , Enfermedades Renales Quísticas/terapia , Fallo Renal Crónico/etiología , Trasplante de Riñón , Masculino , Proteínas de la Membrana/deficiencia , Diálisis Renal , Eliminación de SecuenciaRESUMEN
Thrombotic thrombocytopenic purpura (TTP) is a rare microangiopathic hemolytic anemia (MAHA) defined by mechanical hemolytic anemia, severe thrombocytopenia, and systemic visceral ischemia due to systemic platelet-rich microthrombi. Forty percent of patients with autoimmune TTP experience one or multiple relapses. Patients with refractory TTP are currently managed by corticosteroids, twice-daily PEX, and the anti-CD20 monoclonal antibody rituximab. Herein, we report two cases of severe TTP, refractory to those standard agents. On the basis of the fact that in cases of severe TTP the classical complement pathway is activated, and that the alternative pathway is also involved, both patients underwent eculizumab (anti-C5 monoclonal antibody) therapy. We observed prompt hematological and organ system responses to the eculizumab and the recovery of plasma ADAMTS-13 activity in both cases. Moreover, the fact that both patients discontinued eculizumab, maintaining the response, emphasizes the possibility of its usefulness for limited treatment periods. In conclusion, the diagnostic and therapeutic algorithm in TTP appears complicated by increasing evidence of complement involvement and the eculizumab seems to be a potential agent for refractory patients.
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Proteína ADAMTS13/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Subclinical rejection (SCR) has been variably associated with reduced graft survival, development and progression of interstitial fibrosis/tubular atrophy and chronic allograft nephropathy, but data are controversial concerning SCR treatment in terms of graft survival improvement. In this single-center retrospective study, we enrolled 174 adult kidney transplant recipients with a protocol biopsy performed at 30 days after transplantation to evaluate the incidence rate and risk factors for early SCR and its impact on 10-year graft survival. Five patients showed primary non function and were excluded. Among 159/169 (94.08 %) patients with stable graft function who underwent protocol biopsy, 17 (10.7 %) showed signs of SCR and were treated with low-dose intravenous (i.v.) steroids. Ten patients showed functional impairment, 8 (4.73 %) resulting as acute rejection. At multivariate analysis, donor age [odds ratio (OR) 1.04, 95 % confidence interval (CI) 1.01-1.09], and delayed graft function (DGF) (OR 1.08, 95 % CI 1.03-1.12) were significantly associated with SCR. The 10-year graft survival rate in the SCR group was similar to that in the normal-findings group (76.5 vs. 74.9 % respectively; p = 0.61). At multivariate Cox regression, acute [hazard ratio (HR) 5.22, 95 % CI 1.70-16.01], but not sub-clinical, rejection was independently associated with long-term graft failure. In conclusion, early protocol biopsy is a useful and safe tool to detect early SCR which seems not to affect the long-term survival. We suggest that this could be, probably, linked to early SCR treatment with low dose i.v. steroids.
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Corticoesteroides/uso terapéutico , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto , Trasplante de Riñón/efectos adversos , Adulto , Funcionamiento Retardado del Injerto/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
The pathogenetic role of adiponectin (ADPN) in kidney failure is not yet elucidated, since in vitro and in vivo studies have demonstrated that ADPN exerts both anti-inflammatory and pro-inflammatory effects. Starting from our previous findings demonstrating that HK-2 cells express and secrete ADPN, in this study we investigated the autocrine role of ADPN in tubular inflammatory damage induced by lipopolysaccharide (LPS) and the underlying molecular mechanisms. Firstly, we observed that short-term exposure to LPS enhanced ADPN protein expression as well as the adiponectin receptor ADIPOR1 mRNA content together with its signaling pathway downstream, pAMPK/pERK/pJNK, whose up-regulation status was reversed when ADPN gene knockdown occurred. Interestingly, in the same experimental conditions, we observed that ADPN mediated the nuclear translocation of the transcription factors nuclear factor kappa B (NFkB) and pcFos/pcJun (activator protein 1, AP-1), both induced by the pJNK pathway and involved in tumor necrosis factor (TNF)-α transactivation. Indeed, by transient transfection assay, we observed that the LPS-induced increase of TNF-α promoter activity was abrogated in cells pretreated with the inhibitors of NFkB and AP-1. Collectively our results suggest that in HK-2 cells, ADPN produced upon LPS stimulus could worsen the inflammatory damage in an autocrine-dependent manner.
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Adiponectina/metabolismo , Comunicación Autocrina/efectos de los fármacos , Túbulos Renales Proximales/efectos de los fármacos , Lipopolisacáridos/toxicidad , Nefritis/inducido químicamente , Proteínas Quinasas Activadas por AMP/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Adiponectina/genética , Sitios de Unión , Línea Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Nefritis/genética , Nefritis/metabolismo , Nefritis/patología , Fosforilación , Regiones Promotoras Genéticas , Interferencia de ARN , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transfección , Regulación hacia ArribaRESUMEN
Clinical studies showed that renal expression and serum levels of nerve growth factor (NGF) are increased in renal diseases characterized by progressive fibrosis, a pathologic process in which TGF-ß1 mediates most of the key events leading to tubular epithelial-mesenchymal transition (EMT). However, the pathogenic role of high NGF levels has not yet been elucidated. In this study, we found that in tubular renal cells, HK-2, NGF transcriptionally up-regulated TGF-ß1 expression and secretion and enhanced cell motility by activating EMT markers via its receptors, TrkA and p75(NTR). Interestingly, we observed that TGF-ß1-SMAD pathway activation and the up-regulation of EMT markers NGF-induced were both prevented when knockdown of TGF-ß1 gene occurred and that the pretreatment with an antibody anti-NGF reversed the nuclear translocation of pSMAD3/SMAD4 complex. Collectively, our results demonstrated that NGF promotes renal fibrosis via TGF-ß1-signaling activation, suggesting that in kidney diseases high NGF serum levels could contribute to worsen renal fibrosis.
Asunto(s)
Transición Epitelial-Mesenquimal/fisiología , Fibrosis/patología , Túbulos Renales/fisiología , Factor de Crecimiento Nervioso/metabolismo , Insuficiencia Renal Crónica/patología , Factor de Crecimiento Transformador beta1/metabolismo , Transporte Activo de Núcleo Celular/fisiología , Anticuerpos/inmunología , Línea Celular , Movimiento Celular , Células Epiteliales/citología , Humanos , Factor de Crecimiento Nervioso/sangre , Factor de Crecimiento Nervioso/inmunología , Proteínas del Tejido Nervioso/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Receptor trkA/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Proteína smad3/antagonistas & inhibidores , Proteína smad3/inmunología , Proteína smad3/metabolismo , Proteína Smad4/antagonistas & inhibidores , Proteína Smad4/inmunología , Proteína Smad4/metabolismo , Transcripción Genética/genética , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
UNLABELLED: γ-Secretase proteins complex cleaves the amyloid precursor protein (APP) to generate amyloid-ß (Aß) peptides. Considerable evidence suggests that alterations in genes encoding these proteins exert their influence on the pathogenesis of familial Alzheimer's disease (FAD). Presenilin enhancer-2 gene (PEN-2) is a necessary component of the γ-Secretase complex. Recently, it has been shown that PEN-2 mutations could be involved in Alzheimer's disease (AD). We performed a mutational screening of all PEN-2 coding and promoter regions in a FAD cohort derived from Southern Italy. Four hundred and fifty-two subjects (FAD: 97; CONTROLS: 355) were recruited for this study. We identified for the first time in a key region necessary for the promoter activity a novel 3 bp deletion in a subject with early-FAD. Our genetic data demonstrate that the mutant allele may influence the transcriptional activity of the PEN-2 gene. Although the effective role of the PEN-2 promoter deletion in AD is not entirely clear, these findings might lead to more studies on its functional and genetic role.
Asunto(s)
Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Proteínas de la Membrana/genética , Mutación Missense , Regiones Promotoras Genéticas/genética , Anciano , Secuencia de Bases , Cromatografía Líquida de Alta Presión , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Italia , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , LinajeRESUMEN
A 35-year-old young man displayed Leber's optic neuropathy (LHON) due to T14484C and multiple sclerosis (MS) phenotype that was dominated by symptoms and signs of spinal cord impairment. Magnetic resonance imaging (MRI) revealed demyelinating lesions extending from D6 to D11 in the spinal cord with gadolinium enhancement, while only three linear demyelinating lesions were seen on brain MRI. In the literature, a major involvement of the spinal cord was already reported in three of four male patients with the 14484 LHON mutation who developed MS, but the reasons of this peculiar association remain unknown, and further research in this area is needed.