RESUMEN

ABSTRACT: The incidence of pancreatic cancer is increasing worldwide. Approximately, 60% of patients with pancreatic cancer have distant metastases at the time of diagnosis, of which only 10% can be removed using standard resection. Further, patients derive limited benefits from chemotherapy or radiotherapy. As such, alternative methods to achieve local control have emerged, including permanent iodine-125 seed interstitial brachytherapy. In 2023, the Chinese College of Interventionalists, affiliated with the Chinese Medical Doctor Association, organized a group of multi-disciplinary experts to compose guidelines for this treatment modality. The aim of this conference was to standardize the procedure for permanent iodine-125 seed interstitial brachytherapy, including indications, contraindications, pre-procedural preparation, procedural operations, complications, efficacy evaluation, and follow-up.

Asunto(s)

Braquiterapia , Radioisótopos de Yodo , Neoplasias Pancreáticas , Humanos , Braquiterapia/métodos , Radioisótopos de Yodo/uso terapéutico , Radioisótopos de Yodo/administración & dosificación , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/patología , China , Consenso , Guías de Práctica Clínica como Asunto

RESUMEN

In recent years, a surge in studies investigating N6-methyladenosine (m6A) modification in human diseases has occurred. However, the specific roles and mechanisms of m6A in kidney disease remain incompletely understood. This study revealed that m6A plays a positive role in regulating renal fibrosis (RF) by inducing epithelial-to-mesenchymal phenotypic transition (EMT) in renal tubular cells. Through comprehensive analyses, including m6A sequencing, RNA-seq, and functional studies, we confirmed the pivotal involvement of zinc finger E-box binding homeobox 2 (ZEB2) in m6A-mediated RF and EMT. Notably, the m6A-modified coding sequence of ZEB2 mRNA significantly enhances its translational elongation and mRNA stability by interacting with the YTHDF1/eEF-2 complex and IGF2BP3, respectively. Moreover, targeted demethylation of ZEB2 mRNA using the dm6ACRISPR system substantially decreases ZEB2 expression and disrupts the EMT process in renal tubular epithelial cells. In vivo and clinical data further support the positive influence of m6A/ZEB2 on RF progression. Our findings highlight the m6A-mediated regulation of RF through ZEB2, revealing a novel therapeutic target for RF treatment and enhancing our understanding of the impact of mRNA methylation on kidney disease.

RESUMEN

Renal aging and the subsequent rise in kidney-related diseases are attributed to senescence in renal tubular epithelial cells (RTECs). Our study revealed that the abnormal expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of RNA N6-methyladenosine, is critically involved in cisplatin-induced renal tubular senescence. In cisplatin-induced senescence of RTECs, the promoter activity and transcription of IGF2BP3 is markedly suppressed. It was due to the down regulation of MYC proto-oncogene (MYC), which regulates IGF2BP3 transcription by binding to the putative site at 1852-1863 of the IGF2BP3 promoter. Overexpression of IGF2BP3 ameliorated cisplatin-induced renal tubular senescence in vitro. Mechanistic studies revealed that IGF2BP3 inhibits cellular senescence in RTECs by enhancing cyclin-dependent kinase 6 (CDK6) mRNA stability and increasing its expression. The inhibition effect of IGF2BP3 on tubular senescence is partially reversed by the knockdown of CDK6. Further, IGF2BP3 recruits nuclear cap binding protein subunit 1 (NCBP1) and inhibits CDK6 mRNA decay, by recognizing m6A modification. Specifically, IGF2BP3 recognizes m6A motif "GGACU" at nucleotides 110-114 in the 5' untranslated region (UTR) field of CDK6 mRNA. The involvement of IGF2BP3/CDK6 in alleviating tubular senescence was confirmed in a cisplatin-induced acute kidney injury (AKI)-to-chronic kidney disease (CKD) model. Clinical data also suggests an age-related decrease in IGF2BP3 and CDK6 levels in renal tissue or serum samples from patients. These findings suggest that IGF2BP3/CDK6 may be a promising target in cisplatin-induced tubular senescence and renal failure.

Asunto(s)

Senescencia Celular , Cisplatino , Quinasa 6 Dependiente de la Ciclina , Túbulos Renales , Estabilidad del ARN , Proteínas de Unión al ARN , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Humanos , Senescencia Celular/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/efectos de los fármacos , Quinasa 6 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/genética , Estabilidad del ARN/efectos de los fármacos , Cisplatino/farmacología , Proto-Oncogenes Mas , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Animales , ARN Mensajero/metabolismo , ARN Mensajero/genética

RESUMEN

N1-methyladenosine (m1A) modification is one of the most prevalent epigenetic modifications on RNA. Given the vital role of m1A modification in RNA processing such as splicing, stability and translation, developing a precise and controllable m1A editing tool is pivotal for in-depth investigating the biological functions of m1A. In this study, we developed an abscisic acid (ABA)-inducible and reversible m1A demethylation tool (termed AI-dm1A), which targets specific transcripts by combining the chemical proximity-induction techniques with the CRISPR/dCas13b system and ALKBH3. We successfully employed AI-dm1A to selectively demethylate the m1A modifications at A8422 of MALAT1 RNA, and this demethylation process could be reversed by removing ABA. Furthermore, we validated its demethylation function on various types of cellular RNAs including mRNA, rRNA and lncRNA. Additionally, we used AI-dm1A to specifically demethylate m1A on ATP5D mRNA, which promoted ATP5D expression and enhanced the glycolysis activity of tumor cells. Conversely, by replacing the demethylase ALKBH3 with methyltransferase TRMT61A, we also developed a controllable m1A methylation tool, namely AI-m1A. Finally, we caged ABA by 4,5-dimethoxy-2-nitrobenzyl (DMNB) to achieve light-inducible m1A methylation or demethylation on specific transcripts. Collectively, our m1A editing tool enables us to flexibly study how m1A modifications on specific transcript influence biological functions and phenotypes.

Asunto(s)

Adenosina , Edición de ARN , Adenosina/análogos & derivados , Adenosina/química , Adenosina/metabolismo , Humanos , Ácido Abscísico/farmacología , Ácido Abscísico/química , Ácido Abscísico/metabolismo , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/genética , ARN/metabolismo , ARN/química

RESUMEN

The prevalence of chronic kidney disease (CKD) is highly increasing. Renal fibrosis is a common pathological feature in various CKD. Previous studies showed tubular cell senescence is highly involved in the pathogenesis of renal fibrosis. However, the inducers of tubular senescence and the underlying mechanisms have not been fully investigated. C-X-C motif chemokine receptor 4 (CXCR4), a G-protein-coupled seven-span transmembrane receptor, increases renal fibrosis and plays an important role in tubular cell injury. Whereas, whether CXCR4 could induce tubular cell senescence and the detailed mechanisms have not studied yet. In this study, we adopted adriamycin nephropathy and 5/6 nephrectomy models, and cultured tubular cell line. Overexpression or knockdown of CXCR4 was obtained by injection of related plasmids. We identified CXCR4 increased in injury tubular cells. CXCR4 was expressed predominantly in renal tubular epithelial cells and co-localized with adipose differentiation-related protein (ADRP) as well as the senescence-related protein P16INK4A . Furthermore, we found overexpression of CXCR4 greatly induced the activation of ß-catenin, while knockdown of CXCR4 inhibited it. We also found that CXCR4 inhibited fatty acid oxidation and triggered lipid deposition in tubular cells. To inhibit ß-catenin by ICG-001, an inhibitor of ß-catenin, could significantly block CXCR4-suppressed fatty acid oxidation. Taken together, our results indicate that CXCR4 is a key mediator in tubular cell senescence and renal fibrosis. CXCR4 promotes tubular cell senescence and renal fibrosis by inducing ß-catenin and inhibiting fatty acid metabolism. Our findings provide a new theory for tubular cell injury in renal fibrosis.

Asunto(s)

Riñón , Receptores CXCR4 , Insuficiencia Renal Crónica , beta Catenina , beta Catenina/metabolismo , Senescencia Celular , Células Epiteliales/metabolismo , Ácidos Grasos/metabolismo , Fibrosis , Riñón/patología , Insuficiencia Renal Crónica/patología , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Animales , Ratones

RESUMEN

The ketogenic diet (KD) is a low carbohydrate and high-fat protein diet. It plays a protective role in neurodegenerative diseases by elevating the levels of ketone bodies in blood, regulating central and peripheral metabolism and mitochondrial functions, inhibiting neuroinflammation and oxidative stress, and altering the gut microbiota. However, studies on ketogenic therapy for Parkinson's disease (PD) are still in their infancy. Therefore, we examined the possible protective effect of KD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, examined the mouse gut microbiota and its metabolites, and performed transcriptomics and metabolomics on the substantia nigra of mice. Our results showed that a long-term medium-chain triglyceride KD (MCT-KD) significantly reduced MPTP-induced damage to dopaminergic (DA) neurons, exerted antioxidant stress through the PI3K/Akt/Nrf2 pathway, and reversed oxidative stress in DA neurons. The MCT-KD also reduced mitochondrial loss, promoted ATP production, and inhibited the activation of microglia to protect DA neurons in MPTP-induced PD mice. MCT-KD altered the gut microbiota and consequently changed the metabolism of substantia nigra neurons through gut microbiota metabolites. Compared to the MPTP group, MCT-KD increased the abundance of gut microbiota, including Blautia and Romboutsia. MCT-KD also affects purine metabolism in the substantia nigra pars compacta (SNpc) by altering fecal metabolites. This study shows that MCT-KD has multiple protective effects against PD.

RESUMEN

Acute kidney injury (AKI) is rapidly increasing nowadays and at a high risk to progress into chronic kidney disease (CKD). Of note, men are more susceptive to AKI, suggesting gender differences in AKI patients. However, the underlying mechanisms remain largely unclear. To test it, we adopted two experimental models of AKI, including ischemia/reperfusion injury and rhabdomyolysis, which were constructed in age-matched male and female mice. We found severe damages of tubular apoptosis, mitochondrial dysfunction, and loss of renal function showing in male mice, while female mice only had very mild injury. We further tested the expression of Sirtuins, and found that female mice could preserve more Sirtuin members' expression in case of kidney damage. Among Sirtuin family, Sirtuin 6 was maximally preserved in injured kidney in female mice, suggesting its important role involved in the gender differences of AKI pathogenesis. We then found that knockdown of androgen receptor (AR) attenuated tubular damage, mitochondrial dysfunction and retarded the loss of renal function. Overexpression of Sirtuin 6 also showed similar results. Furthermore, in cultured tubular cells, dihydrotestosterone (DHT) decreased Sirtuin 6 expression and exacerbated cell apoptosis. Ectopic expression of Sirtuin 6 sufficiently inhibited DHT-induced cell apoptosis. Mechanically, we found AR inhibited Sirtuin 6, leading to the repression of binding of Sirtuin 6 with PGC-1α. This resulted in acetylation of PGC-1α and inhibition of its activity, further triggered the loss of mitochondrial homeostasis. Our results provided new insights to the underlying mechanisms of gender differences in AKI, suggesting Sirtuin 6 maybe a new therapeutic target for preventing AKI in male patients.

RESUMEN

BACKGROUND: The systemic inflammatory response index (SIRI), a novel inflammation maker, has proven to be associated with prognostic outcomes in various diseases. However, few studies have been conducted assessing how SIRI may influence outcomes of patients on peritoneal dialysis (PD). Herein, we assessed the predictive value of SIRI on mortality all-cause mortality, including cardiovascular disease (CVD) in PD patients. METHODS: A total of 646 PD patients were enrolled in this study. PD patients received regular PD treatments at the Zhujiang Hospital from 1 January 2011 to 31 December 2018. SIRI values could be computed as follows: neutrophil count × monocyte count/lymphocyte count. Patients were divided into two groups according to the median level of SIRI. Cox regression analysis and Kaplan-Meier methods were applied to analyze the relationship between SIRI and mortality outcomes in PD patients. RESULTS: During the median 31-month follow-up period, 97 (15.0%) PD patients died from all-causes, and 47 (49.0%) died of CVD. Kaplan-Meier analyses revealed that a high SIRI corresponded to the high mortality of all-cause deaths, including CVD (both p < 0.001) in patients on PD. After adjusting for potential confounders, the higher SIRI level was significantly associated with an increased all-cause mortality (HR: 2.007, 95% CI: 1.304-3.088, p = 0.002) and cardiovascular mortality (HR: 2.847, 95% CI: 1.445-5.608, p = 0.002). CONCLUSIONS: SIRI was a promising predictor of mortality in PD patients, with a higher SIRI corresponding to increased risk of mortality.

Asunto(s)

Enfermedades Cardiovasculares , Diálisis Peritoneal , Enfermedades Cardiovasculares/etiología , Humanos , Inflamación , Pronóstico , Estudios Retrospectivos

RESUMEN

Studies on biological functions of RNA modifications such as N6-methyladenosine (m6A) in mRNA have sprung up in recent years, while the roles of N1-methyladenosine (m1A) in cancer progression remain largely unknown. We find m1A demethylase ALKBH3 can regulate the glycolysis of cancer cells via a demethylation activity dependent manner. Specifically, sequencing and functional studies confirm that ATP5D, one of the most important subunit of adenosine 5'-triphosphate synthase, is involved in m1A demethylase ALKBH3-regulated glycolysis of cancer cells. The m1A modified A71 at the exon 1 of ATP5D negatively regulates its translation elongation via increasing the binding with YTHDF1/eRF1 complex, which facilitates the release of message RNA (mRNA) from ribosome complex. m1A also regulates mRNA stability of E2F1, which directly binds with ATP5D promoter to initiate its transcription. Targeted specific demethylation of ATP5D m1A by dm1ACRISPR system can significantly increase the expression of ATP5D and glycolysis of cancer cells. In vivo data confirm the roles of m1A/ATP5D in tumor growth and cancer progression. Our study reveals a crosstalk of mRNA m1A modification and cell metabolism, which expands the understanding of such interplays that are essential for cancer therapeutic application.

Asunto(s)

Glucólisis , ATPasas de Translocación de Protón Mitocondriales , Neoplasias , ARN Mensajero , Dioxigenasa Dependiente de Alfa-Cetoglutarato, Homólogo 3 de AlkB/genética , Dioxigenasa Dependiente de Alfa-Cetoglutarato, Homólogo 3 de AlkB/metabolismo , Glucólisis/genética , Humanos , Metilación , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Neoplasias/enzimología , Neoplasias/genética , ARN Mensajero/metabolismo

RESUMEN

Renal fibrosis is a common feature of various chronic kidney diseases (CKD). However, its underlying mechanism has not been totally clarified. C-X-C motif chemokine receptor (CXCR) family plays a role in renal fibrosis, however, detailed mechanisms have not been elucidated. Here, we report that CXCR2 has a potential role in tubular cell senescence and renal fibrosis, and is associated with ß-catenin-activated mitochondrial dysfunction. CXCR2 is one of most increased members among CXCR family in unilateral ureteral obstruction (UUO) mice. CXCR2 was expressed primarily in tubules and co-localized with p16INK4A, a cellular senescence marker, and ß-catenin. Administration of SB225002, a selective CXCR2 antagonist, significantly inhibited the activation of ß-catenin signaling, restored mitochondrial function, protected against tubular cell senescence and renal fibrosis in unilateral ureteral obstruction (UUO) mice. In unilateral ischemia-reperfusion injury (UIRI) mice, treatment with interlukin-8 (IL-8), the ligand of CXCR2, further aggravated ß-catenin activation, mitochondrial dysfunction, tubular cell senescence and renal fibrosis, whereas knockdown of p16INK4A inhibited IL-8-induced these effects. In vitro, SB225002 inhibited mitochondrial dysfunction and tubular cell senescence. Furthermore, ICG-001, a ß-catenin signaling blocker, significantly retarded CXCR2-induced cellular senescence and fibrotic changes. These results suggest that CXCR2 promotes tubular cell senescence and renal fibrosis through inducing ß-catenin-activated mitochondrial dysfunction.

RESUMEN

Intestinal probiotics are a primary focus area of current medical research. Probiotics such as bifidobacteria and lactobacilli can positively impact obesity and other metabolic diseases by directly or indirectly affecting lipid metabolism. However, the precise mechanisms of these effects remain unclear. In our previous work, the novel strain Lactobacillus reuteri HI120 was isolated and identified. HI120 expresses high levels of linoleic isomerase, resulting in the production of large amounts of conjugated linoleic acid (CLA) when mixed with linoleic acid (LA). As HI120 can efficiently transform LA into CLA, the effect of HI120 on the lipid metabolism in C57BL/6 obese mice was studied and the underlying molecular mechanism was explored in vitro. The results revealed no significant change in the diet, body weight, and serum triglyceride levels in mice. However, serum cholesterol levels were significantly decreased. The underlying mechanism may involve a CLA-mediated reduction in the gene expression levels of NPC1L1, SREBP-2, and HMG-CR, resulting in reduced cholesterol synthesis and absorption. Thus, HI120 can be developed as a potential probiotic formulation. After oral administration, LA from certain food sources can be converted into CLA in the human intestine to contribute to the prevention and treatment of obesity and hyperlipidemia.

RESUMEN

BACKGROUND: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers. However, the role of EZH2 in nonneoplastic diseases, such as kidney diseases, is unknown and has been investigated. MATERIALS AND METHOD: NRK-52E cells were treated with DZNep, a potent inhibitor of EZH2, with different concentrations and for different times to evaluate the apoptosis level of NRK-52E cells by Western blot and Flow cytometry analysis. The binding of EZH2 to the Deptor promoter was determined by ChIP assay. RESULTS: The inhibition of EZH2 with 3-deazaneplanocin A (DZNep), a specific inhibitor of EZH2, led to the apoptosis of NRK-52E cells and the inhibition of mTORC1 and mTORC2 activity. A ChIP assay demonstrated that EZH2 bound the promoter region of Deptor, an endogenous inhibitor of mTORC1 and mTORC2, and regulated the transcription of Deptor by modulating H3K27me3 in its promoter region. Further experiments were performed to examine the effects of EZH2 inhibition on cisplatin-induced injured cells. Cisplatin induced the activation of mTORC1 and mTORC2 and apoptosis in NRK-52E cells, and DZNep inhibited mTORC1 and mTORC2 activity and aggravated cell apoptosis. CONCLUSIONS: These data suggested that EZH2 inhibition increased the transcription of Deptor by modifying H3K27me3 in its promoter region, subsequently inhibited mTORC1 and mTORC2 activities, downregulated the expression of apoptosis suppressor genes, and finally led to apoptosis in renal tubular cells. The inhibition of EZH2 aggravated the cisplatin-induced injury in renal tubular cells by inactivating the mTOR complexes. The present study provides new insight into renal protection and suggests that EZH2 might be a target.

RESUMEN

BACKGROUND: Microinflammation is linked to an increased risk of death due to cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). Although the fibrinogen/albumin ratio (FAR), a novel inflammatory marker, has been shown to predict mortality in various diseases, limited evidence is available for its role in ESRD. The purpose of this study is to explore the prognostic value of the FAR in ESRD patients on peritoneal dialysis (PD). METHODS: In this retrospective observational study, we enrolled patients with ESRD who underwent PD therapy in our hospital between 1 January 2011 and 31 December 2017. The Kaplan-Meier method and Cox proportional hazards models were used to determine the contact between the FAR level and mortality. RESULTS: A total of 562 patients were enrolled in our research. The median FAR was 0.12, and patients were divided into two groups (low FAR group: FAR < 0.12, n = 250, and high FAR group: FAR ≥ 0.12, n = 312) according to the median FAR. Kaplan-Meier curves showed that the cumulative incidences of both all-cause mortality and CVD mortality were significantly higher in patients with FAR ≥ 0.12 (both P < .001). In multivariable analysis, the high FAR group had an important increased risk of all-cause and CVD mortality (HR: 1.80; 95% CI: 1.03-3.14, P = .038 and HR: 2.31; 95% CI: 1.17-4.59, P = .016, respectively). CONCLUSIONS: Our results suggest that a high baseline FAR value is an independent prognostic factor in ESRD patients on PD.

RESUMEN

Mitochondria play important roles in the development of diabetic kidney disease (DKD). The SS peptide is a tetrapeptide that is located and accumulated in the inner mitochondrial membrane; it reduces reactive oxygen species (ROS) and prevents mitochondrial dysfunction. Podocytes are key cellular components in DKD progression. However, whether the SS peptide can exert renal protection through podocytes and the mechanism involved are unknown. In the present study, we explored the mechanisms of the SS peptide on podocyte injury in vivo and in vitro. Compared with the control group, the glomerular podocyte number and expression of WT1 were significantly reduced and TUNEL-positive podocytes were significantly increased in renal tissues in the diabetic rat. These effects were further exacerbated by hypochlorite-modified albumin (HOCl-alb) challenge but prevented by SS-31. In vitro, SS-31 blocked apoptosis in podocyte cell line induced by HOCl-alb. SS-31 prevented oxidative stress and mitochondria-dependent apoptosis signalling by HOCl-alb in vivo and in vitro, as evidenced by the release of cytochrome c (cyt c), binding of apoptosis activated factor-1 (Apaf-1) and caspase-9, and activation of caspases. These data suggest that SS-31 may prevent podocyte apoptosis, exerting renal protection in diabetes mellitus, probably through an apoptosis-related signalling pathway involving oxidative stress and culminating in mitochondria.

Asunto(s)

Apoptosis/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Ácido Hipocloroso/farmacología , Mitocondrias/efectos de los fármacos , Podocitos/efectos de los fármacos , Albúmina Sérica/metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad

RESUMEN

A major feature of the injury sustained by the kidney during obstructive nephropathy is a profound induction of apoptosis in the tubular epithelium. In this study, we explored the central roles of mitochondria and the mechanism of the protective effect of the mitochondrial targeted peptides in tubular cell apoptosis and interstitial fibrosis during obstructive nephropathy. Unilateral ureter obstruction (UUO) was performed on rats, and the animals were randomly assigned to intravenous treatment with normal saline, rat serum albumin (RSA), or HOCl-rat serum albumin (HOCl-RSA) in the presence or absence of SS-31. A sham-operation control group was set up by left ureteral dissociation but not ligation. Compared with the control group, UUO animals displayed fibrotic abnormalities, accompanied by increased expression of collagen-I, fibronectin, α-SMA protein and mRNA in the renal interstitium. They also displayed oxidative stress, as evidenced by increased levels of HOCl-alb, TBARS, and mitochondrial reactive oxygen species (ROS) and a decrease in MnSOD activity in the renal homogenate. Damage to mitochondrial structure and functions was observed, as evidenced by a decrease in the mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and release of cytochrome C (cyto C) from the mitochondria to the cytoplasm. These changes were accompanied by activation of caspase-3, caspase-7, caspase-9, and PARP-1 and increased apoptotic cells in the proximal tubules. HOCl-RSA challenge further exacerbated the above biological effects in UUO animals, but these effects were prevented by administration of SS-31. These data suggested that accumulation of HOCl-alb may promote tubular cell apoptosis and interstitial fibrosis, probably related to mitochondrial oxidative stress and damage, and that SS-31 might contribute to apoptotic pathway suppression via scavenging of ROS in the mitochondria.

Asunto(s)

Antioxidantes/farmacología , Nefritis/tratamiento farmacológico , Oligopéptidos/farmacología , Albúmina Sérica/administración & dosificación , Obstrucción Ureteral/tratamiento farmacológico , Actinas/genética , Actinas/metabolismo , Animales , Caspasas/genética , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibronectinas/genética , Fibronectinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Hipocloroso/química , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Ligadura , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Nefritis/genética , Nefritis/metabolismo , Nefritis/patología , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Albúmina Sérica/química , Transducción de Señal , Uréter/cirugía , Obstrucción Ureteral/genética , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patología

RESUMEN

OBJECTIVES: The association between mean platelet volume/platelet count ratio (MPV/PC) and mortality has been demonstrated in various populations but not in peritoneal dialysis (PD) patients. This study investigated the association between MPV/PC and all-cause and cardiovascular mortality in PD patients. MATERIALS AND METHODS: In this single-center retrospective cohort study, 338 patients who underwent incident PD from January 2006 to June 2014 and had baseline MPV/PC were enrolled and followed until June 30, 2015. RESULTS: The mean patient age was 50.5 ± 14.9 years (58.2% men, 22.8% diabetic). During a median follow-up of 25 (IQR 17 - 39) months, 58 patients died; 30 deaths were due to cardiovascular disease. The patients were stratified into two groups according to the PC, MPV, and MPV/PC quartiles. The all-cause and cardiovascular mortality were compared between both groups. MPV and MPV/PC and all-cause and cardiovascular mortality were significantly associated, even after adjusting for age, gender, Davies score, hemoglobin, albumin, and usage of platelet inhibitors. Only the association between baseline MPV/PC and all-cause and cardiovascular mortality was similar when we examined PC, MPV, and MPV/PC without stratification. In the multivariable adjusted model, each 0.01 increase in MPV/PC was associated with an adjusted hazard ratio (AHR) of 0.67 (95% CI, 0.51 - 0.89) for all-cause mortality and an AHR of 0.63 (95% CI, 0.42 - 0.96) for cardiovascular mortality. CONCLUSION: MPV/PC may be a more reliable and accurate risk factor compared to MPV or PC alone.
.

Asunto(s)

Enfermedades Cardiovasculares/mortalidad , Fallo Renal Crónico/terapia , Diálisis Peritoneal , Anciano , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , China/epidemiología , Femenino , Humanos , Fallo Renal Crónico/complicaciones , Masculino , Volúmen Plaquetario Medio , Persona de Mediana Edad , Recuento de Plaquetas , Pronóstico , Estudios Retrospectivos , Factores de Riesgo

RESUMEN

Oxidative stress aggravates renal fibrosis, a pathway involved in almost all forms of chronic kidney disease (CKD). However, the underlying mechanism involved in the pathogenesis of renal oxidative stress has not been completely elucidated. In this study, we explored the role and mechanism of hypochlorite-modified albumin (HOCl-alb) in mediating oxidative stress and fibrotic response in a remnant-kidney rat model. Five-sixths nephrectomy (5/6 NX) was performed on the rats and then the animals were randomly assigned to intravenous treatment with either vehicle alone, or HOCl-rat serum albumin (RSA) in the presence or absence of SS-31 (administered intraperitoneally). A sham-operation control group was set up concurrently. Compared with the control group, 5/6 NX animals displayed marked mitochondrial (mt) dysfunction, as evidenced by decrease of mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and manganese superoxide dismutase (MnSOD) activity, release of cytochrome C (Cyto C) from mitochondria to the cytoplasm, and increase of mitochondrial reactive oxygen species in renal tissues. They also displayed increased levels of HOCl-alb in both plasma and renal tissues. These changes were accompanied by accumulation of extracellular matrix, worsened proteinuria, deteriorated renal function, and a marked increase of macrophage infiltration along with up-regulation of monocyte chemoattractant protein (MCP)-1 and transforming growth factor (TGF)-ß1 expression. HOCl-alb challenge further exacerbated the above biological effects in 5/6 NX animals, but these adverse effects were prevented by administration of SS-31, a mitochondrial targeted antioxidant peptide. These data suggest that accumulation of HOCl-alb may promote renal inflammation and fibrosis, probably related to mitochondrial oxidative stress and dysfunction and that the mitochondrial targeted peptide SS-31 might be a novel therapy for renal fibrosis and chronic renal failure (CRF).

Asunto(s)

Antioxidantes/farmacología , Ácido Hipocloroso/química , Riñón/efectos de los fármacos , Riñón/patología , Mitocondrias/efectos de los fármacos , Oligopéptidos/farmacología , Albúmina Sérica/farmacología , Animales , Biomarcadores/metabolismo , Citoprotección/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Fibrosis , Riñón/metabolismo , Riñón/fisiología , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Albúmina Sérica/química , Regulación hacia Arriba/efectos de los fármacos

RESUMEN

PURPOSE: The prognostic nutritional index (PNI), a variable based on serum albumin concentration and total lymphocyte count in peripheral blood, is reported as a predictor of mortality in a variety of malignant tumor population. This study is aimed to evaluate whether PNI has prognostic value in patients on peritoneal dialysis (PD). METHODS: This was a single-center, retrospective observational cohort study conducted in incident PD patients from January 1, 2006 to June 30, 2014, and followed until June 30, 2015. The associations of PNI levels with mortality were evaluated by Kaplan-Meier method and Cox proportional hazards models. RESULTS: A total of 345 patients were included in this study. Median PNI level at baseline was 40.7 (range: 18.8-75.5) for all patients. During follow-up, 59 (17.1%) died during follow-up, among which 31 (52.5%) were due to cardiovascular diseases (CVD). In crude analysis, the patients with low PNI had a significant increase risk of CVD and all-cause mortality [hazard ratio (HR) 3.07, 95% confidence interval (CI) 1.51-6.25 and HR 2.18, 95% CI 1.28-3.72, respectively)]. After adjusting age, Davies comorbidity score, hemoglobin and leukocytes, the patients with low PNI still had a significant increased risk of CVD mortality (HR 2.37, 95% CI 1.10-5.12). However, there was no significant difference in risk of all-cause mortality (HR 1.72, 95% CI 0.97-3.06). CONCLUSIONS: Low PNI at initiation of PD was independently associated with an increased CVD mortality.

Asunto(s)

Enfermedades Cardiovasculares/mortalidad , Fallo Renal Crónico/terapia , Estado Nutricional , Diálisis Peritoneal , Adolescente , Adulto , Anciano , Causas de Muerte , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Adulto Joven

RESUMEN

AIM: Membranous nephropathy and minimal change disease (MCD) have been involved in mercury-induced nephrotic syndrome. IgA nephropathy is not known to be a common pathological type. In the present article, we report a case of IgA nephropathy with MCD following exposure to mercury-containing skin lightening cream. MATERIAL AND METHODS: The patient was a 39-year-old woman who presented with nephrotic syndrome. She had a 6-month history of using as many as 8 kinds of skin-lightening creams, and urinary mercury excretion was high. Renal biopsy revealed IgA nephropathy with MCD. The use of cosmetics was stopped and chelation therapy was given. After 4 courses (1 month) of chelation therapy, there was a complete remission of proteinuria and hematuria, and urine tests remained normal during the 5-year follow-up period. RESULTS AND CONCLUSIONS: The unique clinical and pathological features of IgA nephropathy with MCD had raised the controversial question of whether MCD and IgA deposition are separate entities or a common pathophysiology. Repeated renal biopsy and similar cases were helpful and should be carried out as far as possible.
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Asunto(s)

Glomerulonefritis por IGA/inducido químicamente , Intoxicación por Mercurio/complicaciones , Nefrosis Lipoidea/inducido químicamente , Preparaciones para Aclaramiento de la Piel/envenenamiento , Adulto , Quelantes/uso terapéutico , Femenino , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/terapia , Hematuria/etiología , Humanos , Riñón/patología , Riñón/ultraestructura , Intoxicación por Mercurio/tratamiento farmacológico , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/terapia , Síndrome Nefrótico/etiología , Síndrome Nefrótico/terapia , Proteinuria/etiología , Inducción de Remisión , Preparaciones para Aclaramiento de la Piel/química , Unitiol/uso terapéutico

RESUMEN

[This corrects the article DOI: 10.1155/2016/1405924.].