EZH2 promotes angiogenesis in peritoneal dialysis by epigenetically activating SP4 expression in the IL-6/sIL-6R signalling pathway.

Background: Interleukin-6 (IL-6)/soluble IL-6 receptor (sIL-6R) promotes peritoneal angiogenesis by stimulating SP4-mediated vascular endothelial growth factor (VEGF) production in peritoneal dialysis (PD). Moreover, histone methyltransferase enhancer of zeste homologue 2 (EZH2) is involved in IL-6/sIL-6R signalling via the acceleration of vascular endothelial growth factor (VEGF)-induced angiogenesis. However, the molecular mechanism underlying how EZH2 epigenetically activates VFGF expression in IL-6/sIL-6R signalling during PD is still unclear. Methods and Results: In this study, we measured the expression of EZH2, DNMT3B and SP4 in human peritoneal mesothelial cells (HPMCs) treated with IL-6/sIL-6R stimulation and/or EZH2 overexpression, silencing or inhibition. Methylation of the CpG site in the SP4 promoter region and VEGF production were measured under these treatments in HPMCs. Moreover, tube formation in human umbilical vein endothelial cells (HUVECs) was detected following treatment with conditioned media from these stimulated HPMCs. The 5/6 nephrectomy (5/6Nx) rat model was established, and the rats were injected with peritoneal dialysate. EZH2, DNMT3B and SP4 expression and microvessels were analysed in 5/6Nx + PD rats treated with IL-6/sIL-6R and EZH2 overexpression. The results showed that IL-6/sIL-6R and EZH2 overexpression enhanced the expression of EZH2, DNMT3B and SP4, but EZH2 silencing/inhibition reduced these expression levels. The results for VEGF production and tube formation in vitro followed the same trend. IL-6/sIL-6R and EZH2 overexpression increased the methylation percentage of the -170 bp CpG site in the SP4 promoter region in HPMCs. Moreover, IL-6/sIL-6R and EZH2 overexpression stimulated EZH2, DNMT3B and SP4 expression and promoted angiogenesis in 5/6Nx + PD rats. Conclusions: Thus, this study indicated that EZH2 is involved in IL-6/sIL-6R signalling and epigenetically regulates SP4 expression, thereby stimulating VEGF production and angiogenesis in PD. Targeting EZH2 is expected to be a novel therapeutic approach for end-stage renal disease (ESRD) patients with PD treatment.

Butyrate alleviates diabetic kidney disease by mediating the miR-7a-5p/P311/TGF-ß1 pathway.

It has been reported that butyrate played an protect role in diabetic kidney disease (DKD) while the mechanism was still not clear. Transforming growth factor-ß1 (TGF-ß1) is the initial factor which triggers the profibrotic signaling cascades. P311 is an RNA-binding protein, which could stimulate TGF-ß1 translation in several cell types. In our study, we found that supplementary of butyrate alleviated fibrosis and suppressed the expression of TGF-ß1 and P311 in the kidney of db/db mice as well as high glucose (HG)-induced SV40-MES-13 cells. Overexpression of P311 offset the inhibition of butyrate on TGF-ß1 in SV40-MES-13 cells. To make clear the mechanism of butyrate in regulating P311, microRNAs (miRNAs) of the SV40-MES-13 cells were sequenced. We found that miR-7a-5p was significantly decreased in the HG-induced SV40-MES-13 cells and the kidney of db/db mice, while giving butyrate reversed this change. Besides, miR-7a-5p could specifically target the 3' UTR of P311's mRNA and suppressed the expression of P311 in the SV40-MES-13 cells. Giving miR-7a-5p inhibitor blocked the inhibition of butyrate on P311 and TGF-ß1. Introducing the miR-7a-5p agomir into db/db mice alleviated renal fibrosis and inhibit the expression of P311 and TGF-ß1. In conclusion, butyrate alleviated DKD by mediating the miR-7a-5p/P311/TGF-ß1 pathway.

A validation study of UCSD-Mayo risk score in predicting hospital-acquired acute kidney injury in COVID-19 patients.

INTRODUCTION: Acute kidney injury (AKI) in coronavirus disease 2019 (COVID-19) patients is associated with poor prognosis. Early prediction and intervention of AKI are vital for improving clinical outcome of COVID-19 patients. As lack of tools for early AKI detection in COVID-19 patients, this study aimed to validate the USCD-Mayo risk score in predicting hospital-acquired AKI in an extended multi-center COVID-19 cohort. METHODS: Five hundred seventy-two COVID-19 patients from Wuhan Tongji Hospital Guanggu Branch, Wuhan Leishenshan Hospital, and Wuhan No. Ninth Hospital was enrolled for this study. Patients who developed AKI or reached an outcome of recovery or death during the study period were included. Predictors were evaluated according to data extracted from medical records. RESULTS: Of all patients, a total of 44 (8%) developed AKI. The UCSD-Mayo risk score achieved excellent discrimination in predicting AKI with the C-statistic of 0.88 (95%CI: 0.84-0.91). Next, we determined the UCSD-Mayo risk score had good overall performance (Nagelkerke R2 = 0.32) and calibration in our cohort. Further analysis showed that the UCSD-Mayo risk score performed well in subgroups defined by gender, age, and several chronic comorbidities. However, the discrimination of the UCSD-Mayo risk score in ICU patients and patients with mechanical ventilation was not good which might be resulted from different risk factors of these patients. CONCLUSIONS: We validated the performance of UCSD-Mayo risk score in predicting hospital-acquired AKI in COVID-19 patients was excellent except for patients from ICU or patients with mechanical ventilation.

Hypophosphatemia is an independent risk factor for AKI among hospitalized patients with COVID-19 infection.

BACKGROUND: This study sought to investigate incidence and risk factors for acute kidney injury (AKI) in hospitalized COVID-19. METHODS: In this retrospective study, we enrolled 823 COVID-19 patients with at least two evaluations of renal function during hospitalization from four hospitals in Wuhan, China between February 2020 and April 2020. Clinical and laboratory parameters at the time of admission and follow-up data were recorded. Systemic renal tubular dysfunction was evaluated via 24-h urine collections in a subgroup of 55 patients. RESULTS: In total, 823 patients were enrolled (50.5% male) with a mean age of 60.9 ± 14.9 years. AKI occurred in 38 (40.9%) ICU cases but only 6 (0.8%) non-ICU cases. Using forward stepwise Cox regression analysis, we found eight independent risk factors for AKI including decreased platelet level, lower albumin level, lower phosphorus level, higher level of lactate dehydrogenase (LDH), procalcitonin, C-reactive protein (CRP), urea, and prothrombin time (PT) on admission. For every 0.1 mmol/L decreases in serum phosphorus level, patients had a 1.34-fold (95% CI 1.14-1.58) increased risk of AKI. Patients with hypophosphatemia were likely to be older and with lower lymphocyte count, lower serum albumin level, lower uric acid, higher LDH, and higher CRP. Furthermore, serum phosphorus level was positively correlated with phosphate tubular maximum per volume of filtrate (TmP/GFR) (Pearson r = 0.66, p < .001) in subgroup analysis, indicating renal phosphate loss via proximal renal tubular dysfunction. CONCLUSION: The AKI incidence was very low in non-ICU patients as compared to ICU patients. Hypophosphatemia is an independent risk factor for AKI in patients hospitalized for COVID-19 infection.

Endothelin-1 triggers human peritoneal mesothelial cells' proliferation via ERK1/2-Ets-1 signaling pathway and contributes to endothelial cell angiogenesis.

BACKGROUND: Dysfunction of the peritoneum as a dialysis organ may result from progressive membrane injury on peritoneal dialysis (PD). It has been increasingly recognized that the human peritoneal mesothelial cells (HPMCs) play a key role in peritoneal membrane early injury. Recently, it has been reported that bioincompatible PD fluid with high concentrations of glucose and glucose degradation products, low pH, high osmolality, and peritonitis stimulates HPMCs to release endothelin-1 (ET-1). ET-1 causes increased the release of vascular endothelial growth factor, which is important for tumor cell angiogenesis. We hypothesized that activating ET-1 might predict injury of peritoneal membrane. METHODS: HPMCs were isolated from normal omentum. ERK1/2 and Ets-1 phosphorylation were measured by Western blot analysis. HPMC proliferation was detected by the bromodeoxyuridine (BrdU) assay. Capillary networks of tubes formed were photographed under a microscope, and five randomly selected fields from each well were analyzed for total capillary length by using Image J software. RESULTS: MEK-1 blocker significantly abolished the ERK1/2 activation by ET-1, which also triggered phosphorylation, thus activating the transcription factor Ets-1 downstream from ERK1/2. ET-1 was capable to induce HPMC proliferation, which could be attenuated by ET-1 antagonists. Antibody and small interfering RNA mediated blockade of Ets-1 had similar antiproliferative effects. Thus, ET-1 specifically triggered HPMC proliferation via ERK1/2-Ets-1 signaling pathway. VEGF production and endothelial cell angiogenesis were significantly in response to conditioned medium from HPMCs treated with ET-1. CONCLUSIONS: ET-1 triggered HPMC proliferation through the ERK1/2-Ets-1 signaling pathway and contributed to VEGF production and endothelial cell angiogenesis.

Premature termination codon readthrough in human cells occurs in novel cytoplasmic foci and requires UPF proteins.

Nonsense-mutation-containing messenger ribonucleoprotein particles (mRNPs) transit through cytoplasmic foci called P-bodies before undergoing nonsense-mediated mRNA decay (NMD), a cytoplasmic mRNA surveillance mechanism. This study shows that the cytoskeleton modulates transport of nonsense-mutation-containing mRNPs to and from P-bodies. Impairing the integrity of cytoskeleton causes inhibition of NMD. The cytoskeleton thus plays a crucial role in NMD. Interestingly, disruption of actin filaments results in both inhibition of NMD and activation of premature termination codon (PTC) readthrough, while disruption of microtubules causes only NMD inhibition. Activation of PTC readthrough occurs concomitantly with the appearance of cytoplasmic foci containing UPF proteins and mRNAs with nonsense mutations but lacking the P-body marker DCP1a. These findings demonstrate that in human cells, PTC readthrough occurs in novel 'readthrough bodies' and requires the presence of UPF proteins.

CKAP4 contributes to the progression of vascular calcification (VC) in chronic kidney disease (CKD) by modulating YAP phosphorylation and MMP2 expression.

Chronic kidney disease (CKD) is an growing public health concern associated with high mortality rates. The occurrences of vascular calcification (VC) increase concordantly with the progression of CKD.With CKD, hyperphosphatemia promotes intermediate VC, a process that is further facilitated by vascular smooth muscle cells (VSMCs) initiating osteogenic transdifferentiation. The purpose of this study was to determine the involvement of CKAP4 in VC progression. Clinical investigations demonstrate that elevated blood CKAP4 and matrix metallopeptidase 2 (MMP2) levels are related with CKD in individuals. As an in vitro model, mouse VSMCs were extracted and treated with high levels of phosphates (2.5 mmol/L Pi). We also created an in vivo mice model of CKD induced by 5/6 nephrophrectomies and a high-protein diet (High Pi diet). The expression of CKAP4 and MMP2 in both in vitro and in vivo models was significantly higher in VSMCs and calcified aorta in both models. Additionally, in vitro tests indicated that CKAP4 modulates YAP phosphorylation. Simultaneous silencing of CKAP4 and calcium content assay revealed a significant reduction in the VSMCs and calcium content of the aorta. Alizarin red staining and calcium content assay reveled that silencing of CKAP4 reduced the VSMCs and aortic calcification, accompanied with reduced expression of YAP and MMP2. Overall, our study demonstrates for the first time that CKAP4 contributes to VC in CKD by modulating YAP phosphorylation and MMP2 expression.

Butyrate ameliorates skeletal muscle atrophy in diabetic nephropathy by enhancing gut barrier function and FFA2-mediated PI3K/Akt/mTOR signals.

BACKGROUND AND PURPOSE: Muscle protein catabolism in patients with diabetic nephropathy (DN) results in striking loss of muscle proteins, which increases morbidity and mortality risks. Evidence shows that short-chain fatty acids (SCFAs) play an important role in health maintenance and disease development. Recently, the connection between butyrate (a SCFA) and DN has been revealed, although the relationship between butyrate and muscle atrophy remains unclear. EXPERIMENTAL APPROACH: We studied changes in serum butyrate levels in DN patients using metabolomic analyses. In db/db mice, protective effects of butyrate on DN-induced muscle atrophy. were explored. Inhibition of muscle atrophy by butyrate and the underlying mechanism(s) were studied in C2C12 cells exposed to high glucose/lipopolysaccharide (HG/LPS). KEY RESULTS: Butyrate levels in DN patients were significantly decreased. In db/db mice, supplementing normal diet with butyrate improved intestinal barrier function. Concurrently, butyrate alleviated muscle atrophy, promoted PI3K/Akt/mTOR signalling, and suppressed oxidative stress and autophagy in skeletal muscle of db/db mice, and in HG/LPS-exposed C2C12 cells. Further, FFA2 receptors, key components of SCFA signalling, were decreased in skeletal muscle of db/db mice and in HG/LPS-exposed C2C12 cells. Overexpression of FFA2 receptors activated PI3K/Akt/mTOR signalling and inhibited oxidative stress and autophagy in HG/LPS-exposed C2C12 cells. Silencing of FFA2 blocked PI3K/Akt/mTOR signalling that was improved by butyrate, as well as the suppression of oxidative stress and reduction of autophagy. CONCLUSION AND IMPLICATION: Butyrate exerts protective effects on muscle atrophy induced by DN by enhancing intestinal barrier function and activating the FFA2 receptor-mediated PI3K/Akt/mTOR pathway.

Bone marrow mesenchymal stem cell exosomes suppress phosphate-induced aortic calcification via SIRT6-HMGB1 deacetylation.

BACKGROUND: Vascular calcification associated with chronic kidney disease (CKD) can increase the risk of mortality. Elevated serum levels of high mobility group box 1 (HMGB1) promotes vascular calcification in CKD via the Wnt/ß-catenin pathway. Sirtuin 6 (SIRT6) prevents fibrosis in CKD by blocking the expression of ß-catenin target genes through deacetylation. This study aimed to investigate whether the inhibition of vascular calcification by bone marrow mesenchymal stem cell (BMSC)-derived exosomes is related to SIRT6 activity and assess the regulatory relationship between HMGB1 and SIRT6. METHODS: CKD characteristics, osteogenic markers, calcium deposition, and the differential expression of HMGB1 and SIRT6 have been measured in a 5/6 nephrectomized mouse CKD model fed a high-phosphate diet to induce aortic calcification. In vitro assays were also performed to validate the in vivo findings. RESULTS: High phosphate promotes the translocation of HMGB1 from the nucleus to the cytosol and induces the expression of Runx2, osteopontin, and Msx2. However, BMSC-derived exosomes were found to alleviate CKD-related fibrosis and the induction of osteogenic genes although less significantly when SIRT6 expression is suppressed. SIRT6 was found to modulate the cytosol translocation of HMGB1 by deacetylation in vascular smooth muscle cells. CONCLUSION: Our results indicate that BMSC-derived exosomes inhibit high phosphate-induced aortic calcification and ameliorate renal function via the SIRT6-HMGB1 deacetylation pathway.

Thalidomide Suppresses Angiogenesis Through the Signal Transducer and Activator of Transcription 3/SP4 Signaling Pathway in the Peritoneal Membrane.

Peritoneal angiogenesis is the key pathophysiological factor that limits peritoneal ultrafiltration during peritoneal dialysis (PD) in uremic patients. Thalidomide has been confirmed to inhibit angiogenesis by inhibiting the secretion of vascular endothelial growth factor (VEGF), but the exact mechanism by which thalidomide inhibits vascular proliferation during PD is still unclear. Here, the objective of the present study was to investigate whether the reduction in VEGF production by human peritoneal mesothelial cells (HPMCs) was controlled by thalidomide. Stimulation of HPMCs with IL-6 in combination with soluble IL-6 receptor (sIL-6R) promoted VEGF expression and secretion, but these effects were attenuated by thalidomide treatment through a transcriptional mechanism that involved signal transducer and activator of transcription 3 (STAT3) and SP4. Conditioned medium from HPMCs cultured with thalidomide inhibited angiogenic endothelial tube formation, which could be further blocked by silencing SP4 and promoted by overexpressing SP4. In vivo, induction of peritoneal angiogenesis in sham rats, sham+PD rats, 5/6 nephrectomy (5/6Nx) rats, 5/6Nx+PD rats, and 5/6Nx+PD rats intraperitoneally treated with thalidomide showed that thalidomide was involved in the control of several key endothelial-specific targets, including VEGFR2, VEGFR3, SP4, and STAT3 expression and new vessel formation, confirming the role of thalidomide and STAT3/SP4 signaling in these processes. Taken together, these findings identify a novel mechanism that links thalidomide, STAT3/SP4 signaling, and angiogenesis in the peritoneal membrane.

Trimethylamine N-oxide mediated Y-box binding protein-1 nuclear translocation promotes cell cycle progression by directly downregulating Gadd45a expression in a cellular model of chronic kidney disease.

AIMS: Cell cycle arrest plays critical roles in preventing renal tubular epithelial cell (RTEC) injury and maladaptation after the onset of chronic kidney disease (CKD), but the underlying mechanism governing this arrest has not been fully elucidated. This study was designed to determine the underlying role of YB-1 in promoting cell cycle progression and nuclear translocation in HK-2 cells induced by trimethylamine N-oxide (TMAO). MAIN METHODS: YB-1 primarily accumulated in the cytoplasm in HK-2 cells after they were treated with TMAO for 30 min and 6 h. Gene expression was analysed using RNA sequencing in HK-2 cells treated with TMAO. Cell cycle progression was analysed via flow cytometry. Luciferase assay and ChIP-PCR were performed to determine the relationship between transcription factor YB-1 and Gadd45a promoter region. Additionally, mice were fed with TMAO to test renal dysfunction and measure the expression of YB-1, GADD45a and CCNA2 in the kidney sections through immunohistochemistry. KEY FINDINGS: YB-1 primarily accumulated in the cytoplasm in HK-2 cells after they were treated with TMAO for 30 min and 6 h. RNA sequencing analysis showed that the cell cycle checkpoint genes growth arrest and DNA damage (Gadd)45a, Gadd45g, cyclin (Ccn)a2, Ccnb1, Ccne1 and Ccnf were differentially expressed in HK-2 cells after treated with 400 µM TMAO for 30 min. Flow cytometry results demonstrated that cell cycle progression was blocked at the G2/M checkpoint. In animal models, elevated dietary TMAO directly led to progressive renal tubulointerstitial dysfunction and inhibited the expression of YB-1 in kidney. Moreover, YB-1 was determined to regulate Gadd45a expression by directly binding to its promoter region. YB-1 expression was negatively correlated with the expression of Gadd45a and Gadd45g but positively correlated with Ccna2, Ccnb1, Ccne1 and Ccnf in CKD. SIGNIFICANCE: YB-1 may be a reliable molecular target and an effective prognostic biomarker for CKD.

Antitumor activity of a novel series of alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives as PPAR gamma agonists against a panel of human cancer cell lines.

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have shown benefit in treating diabetes mellitus, atherosclerosis and cancer. However, widespread use of thiazolidinediones (TZDs), the clinically used synthetic PPARgamma agonists, has been limited by adverse cardiovascular effects. Consequently, numerous novel non-TZD compounds were synthesized and antidiabetic efficacy was evaluated to identify PPARgamma agonists for potential clinical use. On the other hand, many studies have documented that the antitumor activity of PPARgamma agonists is PPARgamma independent. Here we hypothesized that there might exist some compounds with less PPARgamma agonistic activity or antidiabetic efficacy but potent antitumor activity. In this study, we evaluated the PPARgamma agonistic and antitumor activity of several newly synthesized alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives as PPARgamma agonists in a panel of human cancer cell lines, which showed promising antitumor activity without appreciable PPARgamma agonistic activity. The results of MTT assay revealed that cell viability was inhibited in a dose dependent manner with IC(50) 17.1-55.1 microM for all the novel compounds and rosiglitazone (17.2-165 microM). They induced cell cycle arrest and apoptosis tested by Flow Cytometry. In conclusion, our findings demonstrate that these compounds have potent in vitro cytotoxicity, the possible mechanism of which is through induction of apoptosis and cell cycle arrest.

Antitumor efficacy of two novel non-thiazolidinedione compounds as peroxisome proliferator-activated receptor-gamma agonists in human osteosarcoma cells in vitro.

BACKGROUND: Due to chemotherapy resistance in osteosarcoma subgroups, the prognosis of these patients is still poor, and the development of new agents is of utmost importance. The aim of our study was to test the antitumor effects of two novel alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives as peroxisome proliferator-activated receptor (PPAR) gamma agonists, together with rosiglitazone, a well-known thiazolidinedione (TZD) acting on several osteosarcoma cell lines. METHODS/RESULTS: The MTT assay revealed that cell viability was inhibited in a dose-dependent manner with IC(50) 6.2-15.8 microM for the two novel compounds and rosiglitazone (48.4-83.5 microM). Exposure to DG8 and DH9 at low micromolar concentrations induced a dose-dependent block of DNA synthesis and colony formation. In these antitumor assays, DG8 and DH9 were more effective than rosiglitazone, although the PPARgamma agonistic activity of rosiglitazone is much higher. The SiRNA approach to downregulate specifically PPARgamma in U-2OS cells did not affect the cytotoxic efficiency of either the two novel compounds or rosiglitazone. CONCLUSION: These observations suggest that non-TZDs with less PPARgamma agonistic activity might show more potent antitumor efficacy independent of PPARgamma in human osteosarcoma cells, which supports the possibility that they could be beneficial in the treatment of osteosarcoma patients.

High Mobility Group Box 1 Promotes Aortic Calcification in Chronic Kidney Disease via the Wnt/ß-Catenin Pathway.

Vascular calcification (VC) is common in chronic kidney disease (CKD), where cardiovascular mortality remains the leading cause of death. Here, we examined the role of high-mobility group box1 (HMGB1), a nuclear DNA-binding protein involved in inflammation, in aortic calcification and renal dysfunction induced by high phosphate in a mouse model of CKD induced by 5/6 nephrectomy. HMGB1 and kidney function markers were measured by ELISA in the serum of CKD patients and in CKD mice. Sections of the aortas of mice were analyzed by immunofluorescence and Alizarin red staining, and protein lysates were generated to analyze the expression of related proteins in response to silencing of HMGB1 or ß-catenin by western blotting. Our results showed that serum HMGB1 levels were significantly higher in CKD patients than in healthy controls and related to disease stage. High phosphate promoted the translocation of HMGB1 from the nucleus to the cytosol and aortic calcification in CKD mice in vivo, whereas HMGB1 knockdown ameliorated part of renal and vascular function. ß-catenin silencing reversed high phosphate-induced calcification and restored renal marker levels. Taken together, our results suggest that HMGB1 is involved in VC associated with CKD via a mechanism involving the ß-catenin.

Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability.

Nonsense-mediated mRNA decay (NMD) is responsible for the degradation of mRNAs with a premature termination codon (PTC). The role of this system in cancer is still quite poorly understood. In the present study, we evaluated the functional consequences of NMD activity in a subgroup of colorectal cancers (CRC) characterized by high levels of mRNAs with a PTC due to widespread instability in microsatellite sequences (MSI). In comparison to microsatellite stable (MSS) CRC, MSI CRC expressed increased levels of two critical activators of the NMD system, UPF1/2 and SMG1/6/7. Suppression of NMD activity led to the re-expression of dozens of PTC mRNAs. Amongst these, several encoded mutant proteins with putative deleterious activity against MSI tumorigenesis (e.g., HSP110DE9 chaperone mutant). Inhibition of NMD in vivo using amlexanox reduced MSI tumor growth, but not that of MSS tumors. These results suggest that inhibition of the oncogenic activity of NMD may be an effective strategy for the personalized treatment of MSI CRC.

The benefits of peritoneal dialysis (PD) solution with low-glucose degradation product in residual renal function and dialysis adequacy in PD patients: A meta-analysis / Beneficios de la solución de diálisis peritoneal (DP), con producto de degradación bajo en glucosa, en la función renal residual y la adecuación de la diálisis en pacientes en DP: un metanálisis

Abstract The peritoneal effects of low-glucose degradation product (GDP)-containing peritoneal dialysis (PD) solutions have been extensively described. To systematically evaluate the efficacy and safety of low GDP solution for PD patients, specifically the effect on residual renal function (RRF) and dialysis adequacy, we conducted a meta-analysis of the published randomized controlled trials (RCTs). Different databases were searched for RCTs that compared low GDP-PD solutions with conventional PD solutions in the treatment of PD patients with continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD). The outcomes of RCTs should include RRF and may include small solute clearance, peritoneal transport status, nutritional status, and all-cause mortality. Seven studies (632 patients) were included. Compared with the conventional solution, low-GDP solution preserved RRF in PD patients over time (MD 0.66 mL/min, 95% CI 0.34 to 0.99; p<0.0001), particularly in one year of treatment (p<0.01), and improved weekly Kt/V (MD 0.11, 95% CI 0.05 to 0.17; p=0.0007) without an increased 4-hour D/Pcr (MD 0.00, 95% CI -0.02 to 0.02; p=1.00). Notably, the MD of RRF and urine volume between the two groups tended to decrease as time on PD progressed up to 24 months. Patients using low GDP PD solutions did not have an increased risk of all-cause mortality (MD 0.97, 95% CI 0.50 to 1.88; p=0.93). Our meta-analysis confirms that the low GDP PD solution preserves RRF, improves the dialysis adequacy without increasing the peritoneal solute transport rate and all-cause mortality. Further trials are needed to determine whether this beneficial effect can affect long-term clinical outcomes.

Resumen Los efectos peritoneales de las soluciones de diálisis peritoneal (DP) que contienen productos de degradación bajos en glucosa (PIB) se han descrito ampliamente. Para evaluar sistemáticamente la eficacia y la seguridad de la solución de PIB bajo para pacientes en DP, específicamente el efecto sobre la función renal residual (RRF) y la adecuación de la diálisis, realizamos un metanálisis de los ensayos controlados aleatorios (ECA) publicados. Se realizaron búsquedas en diferentes bases de datos de ECA que compararan la solución de DP de bajo PIB con la solución de DP convencional en el tratamiento de pacientes con EP con CAPD y APD. Los resultados de los ECA deben incluir la RRF y pueden incluir la depuración de solutos pequeños, el estado nutricional, el estado del transporte peritoneal y la mortalidad por todas las causas. Se incluyeron siete estudios (632 pacientes). En comparación con la solución convencional, la solución de bajo PIB preservó la FRR en pacientes con EP a lo largo del tiempo (DM 0,66 mL/min, IC del 95%: 0,34 a 0,99; p<0,0001), particularmente en un año de tratamiento (p<0,01), y mejoró el Kt/V semanal (DM 0,11, IC del 95%: 0,05 a 0,17; p = 0,0007), sin un aumento de D/Pcr a las 4 horas (DM 0,00, IC del 95%: -0,02 a 0,02; p = 1,00). Los pacientes que usaron una solución para DP con bajo contenido de GDP no tuvieron un mayor riesgo de mortalidad por todas las causas (DM 0,97; IC del 95%: 0,50 a 1,88; p = 0,93). Nuestro metanálisis confirma que la solución de DP de bajo PIB preserva la FRR, mejora la adecuación de la diálisis sin aumentar la tasa de transporte peritoneal de solutos y la mortalidad por todas las causas. Se necesitan más ensayos para determinar si este efecto beneficioso puede afectar los resultados clínicos a largo plazo.

Rescue of nonsense mutations by amlexanox in human cells.

BACKGROUND: Nonsense mutations are at the origin of many cancers and inherited genetic diseases. The consequence of nonsense mutations is often the absence of mutant gene expression due to the activation of an mRNA surveillance mechanism called nonsense-mediated mRNA decay (NMD). Strategies to rescue the expression of nonsense-containing mRNAs have been developed such as NMD inhibition or nonsense mutation readthrough. METHODS: Using a dedicated screening system, we sought molecules capable to block NMD. Additionally, 3 cell lines derived from patient cells and harboring a nonsense mutation were used to study the effect of the selected molecule on the level of nonsense-containing mRNAs and the synthesis of proteins from these mutant mRNAs. RESULTS: We demonstrate here that amlexanox, a drug used for decades, not only induces an increase in nonsense-containing mRNAs amount in treated cells, but also leads to the synthesis of the full-length protein in an efficient manner. We also demonstrated that these full length proteins are functional. CONCLUSIONS: As a result of this dual activity, amlexanox may be useful as a therapeutic approach for diseases caused by nonsense mutations.

Long-term antibiotics for the prevention of recurrent urinary tract infection in children: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of long-term prophylactic antibiotics for recurrent urinary tract infection (UTI) in children through meta-analysis of randomised controlled trials. METHODS: Electronic databases and reference lists of review articles were searched for relevant trials. Outcome measures were recurrence of symptomatic UTI, repeat positive urine culture, new or deteriorated renal scarring and adverse events during and after treatment. RESULTS: Eleven trials with 2046 patients were identified. Analysis suggested rates of recurrent symptomatic UTI were not significantly different between antibiotic (12.4%) and control groups (15.5%) (RR 0.83, 95% CI 0.66 to 1.05). Subsequent sensitivity and subgroup analyses according to patient vesicoureteric reflux (VUR) status, patient characteristics, history of UTI, site of UTI and duration of treatment also produced no significant effect. However, when trials were divided by study quality, only in trials with adequate allocation concealment was recurrent symptomatic UTI reduced by antibiotic prophylaxis. Prophylactic antibiotics reduced the risk of repeat positive urine culture (RR 0.50, 95% CI 0.34 to 0.74). A subgroup analysis limited to patients without VUR showed similar results (0.52, 0.33 to 0.83), whereas patients with VUR showed a non-significant decrease (0.82, 0.61 to 1.09) in risk of repeat positive urine culture. Seven studies reported the rate of new or deteriorated renal scars and showed no significant difference (0.95, 0.51 to 1.78). CONCLUSIONS: Evidence is lacking that prophylactic antibiotics reduce the incidence of recurrent childhood UTI. Since the reviewed studies had limitations in methodological design, large scale, high quality, placebo-controlled, double-blind trials are required.

Rosiglitazone inhibits cell proliferation by inducing G1 cell cycle arrest and apoptosis in ADPKD cyst-lining epithelia cells.

Abnormal proliferation is an important pathological feature of autosomal dominant polycystic kidney disease (ADPKD). Many drugs inhibiting cell proliferation have been proved to be effective in slowing the disease progression in ADPKD. Recent evidence has suggested that peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have anti-neoplasm effects through inhibiting cell growth and inducing cell apoptosis in various cancer cells. In the present study, we examined the expression of PPARgamma in human ADPKD kidney tissues and cyst-lining epithelial cell line, and found that the expression of PPARgamma was greater in ADPKD kidney tissues and cyst-lining epithelial cell line than in normal kidney tissues and human kidney cortex (HKC) cell line. Rosiglitazone inhibited significantly proliferation of cyst-lining epithelial cells in a concentration- and time-dependent manner. These effects were diminished by GW9662, a specific PPARgamma antagonist. Cell cycle analysis showed a G0/G1 arrest in human ADPKD cyst-lining epithelial cells with rosiglitazone treatment. Analysis of cell cycle regulatory proteins revealed that rosiglitazone decreased the protein levels of proliferating cell nuclear antigen, pRb, cyclin D1, cyclin D2 and Cdk4 but increased the levels of p21 and p27 in a dose-dependent manner. Rosiglitazone also induced apoptosis in cyst-lining epithelial cells, which was correlated with increased bax expression and decreased bcl-2 expression. These results suggest PPARgamma agonist might serve as a promising drug for the treatment of ADPKD.