The Effect of Cr Addition on the Strength and High Temperature Oxidation Resistance of Y2O3 Dispersion Strengthened Mo Composites.

Y2O3 dispersion-strengthened Molybdenum (Mo) composites were prepared by the mechanical alloying of Mo and Y powders then consolidation by spark plasma sintering. The effects of Chromium (Cr) addition (0 wt. %, 5 wt. %, 10 wt. % and 15 wt. %, respectively) on the mechanical performance and high-temperature oxidation resistance of Mo-Y2O3 were investigated. The introduction of Cr had a significant influence on the mechanical property and oxidation resistance of the Mo-Y2O3 composite. The highest bending strength reached 932 MPa when the addition of Cr content was 5 wt. % (Mo-5Cr-1Y sample). This improvement is likely attributable to the dual mechanism of grain refinement and solid solution strengthening. Moreover, the Mo-5Cr-1Y sample showed the thinnest oxide layer thickness after high-temperature oxidation tests, and exhibited the best oxidation resistance performance compared with the other samples. First principle calculation reveals that Cr could improve the Mo-MoO3 interface bonding to prevent rapid spalling of the oxide layer. Meanwhile, Cr also facilitates the formation of the dense Cr2(MoO4)3 layer on the surface, which can inhibit further oxidation.

Assessing the quality consistency of red yeast medicinal material by five-wavelength fusion fingerprint and ultraviolet quantum fingerprint corresponding with antioxidant activity analysis.

In this study, a five-wavelength fusion fingerprint (FWFFT) combined with all-ultraviolet(UV) and antioxidant methods was used to explore the quality consistency of red yeast (RYT) samples. 1,1-Diphenyl-2-picrylhydrazyl Free Radical (DPPH) was used for antioxidant experiments, combined with high performance liquid chromatography (HPLC), and grey correlation analysis (GCA) was performed with chromatographic peak area. The results showed that multi-wavelength fusion technology compensates for the shortcomings of single-wavelength technology, and the combination with UV avoids of the one-sidedness of single technology. Simultaneously, the fingerprint peak of the sample and the antioxidant activity had a high correlation, and the antioxidant activity had a corresponding relationship with the content of the two controls. This study provides a comprehensive and reliable method for the quality consistency evaluation of traditional Chinese medicines (TCM).

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.

Autophagy-dependent Na+-K+-ATPase signalling and abnormal urate reabsorption in hyperuricaemia-induced renal tubular injury.

Increasing evidence indicates that hyperuricaemia (HUA) is not only a result of decreased renal urate excretion but also a contributor to kidney disease. Na+-K+-ATPase (NKA), which establishes the sodium gradient for urate transport in proximal tubular epithelial cells (PTECs), its impairment leads to HUA-induced nephropathy. However, the specific mechanism underlying NKA impairment-mediated renal tubular injury and increased urate reabsorption in HUA is not well understood. In this study, we investigated whether autophagy plays a key role in the NKA impairment signalling and increased urate reabsorption in HUA-induced renal tubular injury. Protein spectrum analysis of exosomes from the urine of HUA patients revealed the activation of lysosomal processes, and exosomal expression of lysosomal-associated membrane protein-2 was associated with increased serum levels and decreased renal urate excretion in patients. We demonstrated that high uric acid (UA) induced lysosome dysfunction, autophagy and inflammation in a time- and dose-dependent manner and that high UA and/or NKA α1 siRNA significantly increased mitochondrial abnormalities, such as reductions in mitochondrial respiratory complexes and cellular ATP levels, accompanied by increased apoptosis in cultured PTECs. The autophagy inhibitor hydroxychloroquine (HCQ) ameliorated NKA impairment-mediated mitochondrial dysfunction, Nod-like receptor pyrin domain-containing protein 3 (NLRP3)-interleukin-1ß (IL-1ß) production, and abnormal urate reabsorption in PTECs stimulated with high UA and in rats with oxonic acid (OA)-induced HUA. Our findings suggest that autophagy plays a pivotal role in NKA impairment-mediated signalling and abnormal urate reabsorption in HUA-induced renal tubular injury and that inhibition of autophagy by HCQ could be a promising treatment for HUA.

Comprehensive Analysis of the Butyrate-Metabolism-Related Gene Signature in Tumor Microenvironment-Infiltrating Immune Cells in Clear Cell Renal Cell Carcinoma.

A wealth of experimental evidence has validated that butyrate is capable of inhibiting tumorigenesis, while the potential role of butyrate metabolism in the tumor immune microenvironment (TIME) has been rarely explored. This study aims to explore the potential of butyrate-metabolism-related genes as prognostic biomarkers and their correlations with immune infiltrates in clear cell renal cell carcinoma (ccRCC) patients. Based on The Cancer Genome Atlas dataset (TCGA; n = 539), a total of 22 differentially expressed genes (DEGs) related with butyrate metabolism in ccRCC and normal samples were identified. Among them, a prognostic signature involving six butyrate-metabolism-related genes was created (Bu-Meta-GPS) in the training set (n = 271) and validation set (n = 268), and risk scores were calculated based on them. ccRCC patients with high-risk scores exhibited an unfavorable prognosis, high immunoscore, upregulated immuno-oncological targets (PD1, PD-L1, CTLA4, and CD19), and distinct immune-cell infiltration than those with low-risk scores. High-risk ccRCC patients without radiotherapy had a better survival rate than radiotherapy-treated patients. The negative regulation of cytokine production and cytokine-mediated signaling pathways was remarkably enriched in ccRCC patients with high-risk scores. A nomogram was then formulated to assess the overall survival (OS) of ccRCC patients. In summary, we illuminated the key role of butyrate metabolism in ccRCC TIME. The developed Bu-Meta-GPS was a sensitive predictive biomarker for the prognosis of ccRCC, which also provided new perspectives in improving immunotherapeutic efficacy.

Low serum uric acid levels are associated with incidence and severity in trigeminal neuralgia.

BACKGROUND: Uric acid is a natural antioxidant, and low levels of uric acid have been reported to be a potential risk factor in the development of nervous system diseases. Herein, we investigated whether uric acid levels play a role in trigeminal neuralgia (TN). METHODS: We conducted a cohort study to compare the serum uric acid levels of patients with TN and healthy controls. We also analyzed the impact of uric acid levels on the risk of TN and symptom severity. RESULTS: In comparison to control participants (n = 133), uric acid levels were remarkably decreased in patients with TN (n = 181). Uric acid (OR = 0.989; 95% CI 0.986-0.993; P < 0.001) was also determined as a protective factor against TN based on multivariate logistic regression models. Furthermore, nonlinear relationships between serum uric acid levels and TN incidence rate and between that and the Barrow Neurological Institute (BNI) grading were observed. CONCLUSIONS: Our study is the first to show a relationship between serum uric acid levels and TN. Specifically, low serum uric acid levels were associated with an increased risk of TN and more severe clinical symptoms. We expect that these findings will provide new insights into the prevention and treatment of TN.

DNA methyltransferase 1 knockdown reverses PTEN and VDR by mediating demethylation of promoter and protects against renal injuries in hepatitis B virus-associated glomerulonephritis.

BACKGROUND: Aberrant DNA methylation patterns, including hypermethylation of key genes that inhibit fibrosis and inflammation, have been described in human kidney diseases. However, the role of DNA methyltransferase 1 (DNMT1) in hepatitis B virus-associated glomerulonephritis (HBV-GN) remains unclear. METHODS: We explored the underlying mechanism by establishing HBV X protein (HBx) overexpressing renal tubular epithelial (HK-2) cells and human podocytes with DNMT1 knockdown. Using RNA-sequencing to determine the downstream targets of DNMT1 and evaluate its levels of promoter methylation. HBV transgenic mice were used to examine the effects of DNMT1 inhibitor on renal in vivo. RESULTS: DNMT1 was significantly upregulated in the renal tissue of HBV-GN patients, accompanied by injuries of HK-2 cells and podocytes. HBx markedly upregulated DNMT1 and induced epithelial-mesenchymal transition (EMT) and inflammation in HK-2 cells and human podocytes. This increased DNMT1 expression was attenuated after DNMT1 knockdown, accompanied by restored HK-2 cells and podocyte injuries resulting from the activation of PI3K/Akt/mTOR and nuclear factor-kappa B (NF-κB) pathways. Hypermethylation of the phosphatase and tensin homolog (PTEN) promoter and vitamin D receptor (VDR) was induced in HBx-overexpressing HK-2 cells and podocytes, respectively, whereas DNMT1 knockdown effectively corrected these alterations. Furthermore, PTEN and VDR ablation resulted in marked EMT and inflammation induction in HBx-overexpressing HK-2 cells and human podocytes even with DNMT1 knockdown. Downregulation of the PI3K/Akt/mTOR-related pathway attenuated HBx-induced EMT and inflammation in HK-2 cells. Luciferase reporter assay revealed VDR as a direct target of the Snail family transcriptional repressor 1 (SNAI1) in HBx-overexpressing podocytes. DNA methylation inhibitor 5-azacytidine alleviated urinary protein and renal inflammation in HBV transgenic mice via PTEN-PI3K/Akt signaling and VDR signaling axis. CONCLUSIONS: Our study clarifies the potential epigenetic mechanisms underlying HBx-induced renal injuries in HBV-GN and the renoprotective effects of inhibiting DNMT1, which can provide important insights into the development of treatments for HBV-GN.

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.

Association of Serum Uric Acid Levels in Meige's Syndrome.

Uric acid (URIC) is a natural antioxidant, and it has been shown that low levels of URIC could be a risk factor for the development of Parkinson's disease. Our aim was to investigate whether URIC also plays a role in Meige's syndrome (MS). We conducted a cohort study to compare serum URIC levels between patients with MS and healthy controls. In addition, we analyzed the impact of URIC on the risk of MS and symptom severity. Compared with normal subjects, URIC content was remarkably decreased in MS patients. In addition, URIC was regarded as a protective factor for MS, as verified by multivariate logistic regression models. We also found non-linear relationships between the levels of serum URIC and the incidence rate of MS and the Burke-Fahn-Marsden dystonia rating scale score. Our study is the first to show a connection between serum URIC levels and MS. Low serum URIC levels indicate an increased risk of MS incidence and more severe clinical symptoms. Our findings provide new insights into the prevention and treatment of MS.

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.

Cox4i2 Triggers an Increase in Reactive Oxygen Species, Leading to Ferroptosis and Apoptosis in HHV7 Infected Schwann Cells.

Emerging evidence suggests that reactive oxygen species (ROS) play a significant role in the pathogenesis of peripheral nerve damage. Our previous study indicated that human herpesvirus 7 (HHV7) induces Bell's palsy. However, the specific mechanism underlying the effects of ROS in HHV7 infection-induced facial nerve damage is unknown. In this study, we established a rat FN model by inoculating an HHV7 virus solution. The facial grading score and LuxolFastBlue (LFB) staining were used to assess the success of the model. Using mRNA-sequencing analysis, we found that the expression of Complex IV Subunit 4 Isoform 2 (Cox4i2) increased in infected Schwann cells (SCs). Cox4i2 was suggested to increase COX activity, thereby promoting ROS production. The changes in the endogenous oxidant and antioxidant system were assessed, and the results showed that oxidative stress increased after HHV7 infection in vivo and in vitro. However, we found that oxidative injury was relieved after the transfection of shCox4i2 in HHV7-treated SCs by evaluating cell death, cell proliferation, and the ROS level as well as the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). Furthermore, we hypothesised that Cox4i2 loss would attenuate HHV7-induced ferroptosis and apoptosis, which are closely related to ROS in SCs. Our research illustrated that the knockdown of Cox4i2 suppresses HHV7-induced RSC96 cell ferroptosis as well as apoptosis via the ERK signalling pathway. Overall, several in vitro and in vivo methods were adopted in this study to reveal the new mechanism of ROS-induced and Cox4i2-mediated apoptosis and ferroptosis in HHV7 infected SCs.

Gegen Qinlian Decoction Ameliorates Hyperuricemia-Induced Renal Tubular Injury via Blocking the Inflammatory Signaling Pathway.

Background: Gegen Qinlian decoction (GGQLD) is a typical traditional Chinese medicine (TCM) prescription documented in Shang Han Lun. Clinically, GGQLD has been utilized to manage the inflammatory symptoms of metabolic diseases and to protect against renal damage in China. In the present study, a hypothesis was proposed that the multi-target solution of GGQLD produced anti-inflammatory effects on ameliorating hyperuricemia (HUA). Methods: A total of 30 primary HUA patients receiving GGQLD treatment (two doses daily) for 4 weeks were selected. Then, differences in uric acid (UA) levels and expression of peripheral blood mononuclear cells (PBMCs) and urinary exosomes before and after treatment were analyzed. The therapeutic indexes for the active ingredients in GGQLD against HUA were confirmed through pharmacological subnetwork analysis. Besides, the HUA rat model was established through oral gavage of potassium oxonate and treated with oral GGQLD. In addition, proximal tubular epithelial cells (PTECs) were stimulated by UA and intervened with GGQLD for 48 h. Subsequently, RNA-seq, flow cytometry, and confocal immunofluorescence microscopy were further conducted to characterize the differences in UA-mediated inflammation and apoptosis of human renal tubular epithelial cells pre- and post-administration of GGQLD. In the meanwhile, quantitative real-time PCR (qPCR) was carried out to determine gene expression, whereas a western blotting (WB) assay was conducted to measure protein expression. Results: Our network analysis revealed that GGQLD treated HUA via the anti-inflammatory and antiapoptotic pathways. Additionally, NLPR3 expression significantly decreased in PBMCs and urinary exosomes of HUA patients after GGQLD treatment. In vivo, GGQLD treatment alleviated HUA-induced renal inflammation, which was associated with decreased expression of NLRP3 inflammasomes and apoptosis-related mRNAs. Moreover, GGQLD promoted renal UA excretion by inhibiting the activation of GSDMD-dependent pyroptosis induced by NLRP3 inflammasomes and by reducing apoptosis via the mitochondrial apoptosis signaling pathway in vitro. Conclusion: This study indicates that GGQLD efficiently reduces inflammatory responses while promoting UA excretion in HUA. Our findings also provide compelling evidence supporting the idea that GGQLD protects against the UA-mediated renal tubular epithelial cell inflammation through the mitochondrial apoptosis signaling pathways. Taken together, these findings have demonstrated a novel therapeutic method for the treatment of HUA.

The Association between Urinary Glucose and Renal Uric Acid Excretion in Non-diabetic Patients with Stage 1-2 Chronic Kidney Disease.

Aims: To test the hypothesis that in non-diabetic patients with early-stage chronic kidney disease (CKD), the renal excretion of urate and glucose transportation are coupled and interconnected. Methods: A cross-sectional study of 255 non-diabetic participants with stage 1-2 CKD recruited from our department was conducted. Spearman's correlation and multiple linear regression analyses were used to study the correlation between urinary glucose and renal uric acid excretion. ANOVA was used to compare urinary uric acid excretion among three tertiles of urinary glucose (UG; UG1: UG<0.24 mmol/24 h/1.73 m2, UG2: 0.24 mmol/24 h/1.73 m2≤ UG≤0.55 mmol/24 h/1.73 m2, and UG3: UG>0.55 mmol/24 h/1.73 m2), the fractional excretion of glucose (FEG; FEG1: FEG<0.04%, FEG2: 0.04%≤FEG≤0.09%, and FEG3: FEG>0.09%) and the excretion of glucose per volume of glomerular filtration (EgGF; EgGF1: EgGF<1.95 µmol/L, EgGF2: 1.95 µmol/L≤ EgGF≤3.99 µmol/L, and EgGF3: EgGF>3.99 µmol/L). Results: According to the multiple linear regression analysis, FEG and EgGF were positively correlated with the excretion of uric acid per volume of glomerular filtration (EurGF) after adjusting for confounding factors. The EurGF levels in the highest tertiles of UG, FEG and EgGF were higher than those in the lowest tertiles of UG, FEG and EgGF. Conclusion: Urinary glucose excretion is closely related to renal excretion of uric acid in non-diabetic patients with stage 1-2 CKD.

Efficacy of different urinary uric acid indicators in patients with chronic kidney disease.

BACKGROUND: Mounting studies have shown that hyperuricemia is related to kidney diseases through multiple ways. However, the application of urinary uric acid indicators in patients with reduced renal function is not clear. In this study, we aim to determine the effects of renal function on various indicators reflecting uric acid levels in patients with chronic kidney disease (CKD). METHODS: Anthropometric and biochemical examinations were performed in 625 patients with CKD recruited from Dept of Nephrology of Huadong hospital affiliated to Fudan University. Multiple regression analyses were used to study correlations of the estimated glomerular filtration rate (eGFR) with serum uric acid (SUA) and renal handling of uric acid. For further study, smooth curve plots and threshold effect analyses were applied to clarify associations between renal function and uric acid levels. RESULTS: The nonlinear relationships were observed between eGFR and urinary uric acid indicators. The obvious inflection points were observed in smooth curve fitting of eGFR and fractional excretion of uric acid (FEur), excretion of uric acid per volume of glomerular filtration (EurGF). In subsequent analyses where levels of eGFR< 15 mL/min/1.73m2 were dichotomized (CKD5a/CKD5b), patients in the CKD5a showed higher levels of FEur and EurGF while lower levels of urinary uric acid excretion (UUA), clearance of uric acid (Cur) and glomerular filtration load of uric acid (FLur) compared with CKD5b group (all P < 0.05). And there was no significant difference of SUA levels between two groups. On the other hand, when eGFR< 109.9 ml/min/1.73 m2 and 89.1 ml/min/1.73 m2, the resultant curves exhibited approximately linear associations of eGFR with Cur and FLur respectively. CONCLUSION: FEur and EurGF showed significantly compensatory increases with decreased renal function. And extra-renal uric acid excretion may play a compensatory role in patients with severe renal impairment to maintain SUA levels. Moreover, Cur and FLur may be more reliable indicators of classification for hyperuricemia in CKD patients.

The association of renal tubular inflammatory and injury markers with uric acid excretion in chronic kidney disease patients.

AIM: To investigate the correlation of renal tubular inflammatory and injury markers with renal uric acid excretion in chronic kidney disease (CKD) patients. METHODS: Seventy-three patients with CKD were enrolled. Fasting blood and morning urine sample were collected for routine laboratory measurements. At the same time, 24 h of urine was collected for urine biochemistry analyses, and 10 ml was extracted from the 24-h urine sample to further detect renal tubular inflammatory and injury markers, including interleukin-18 (IL-18), interleukin 1ß (IL-1ß), neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). The patients were divided into three tertile groups according to their 24-h urinary uric acid (24-h UUA) levels (UUA1: 24-h UUA ≤ 393.12 mg; UUA2: 393.12 < 24-h UUA ≤ 515.76 mg; UUA3: 24-h UUA > 515.76 mg). The general clinical and biochemical indexes were compared. Multivariable linear regression models were used to test the association of IL-18/Urinary creatinine concentration (IL-18/CR), IL-1ß/CR, NGAL/CR and KIM-1/CR with renal uric acid excretion indicators. RESULTS: All of tested renal tubular inflammation- and injury-related urinary markers were negatively associated with 24-h UUA and UEUA, and the negative correlation still persisted after adjusting for multiple influencing factors including urinary protein and eGFR. Further group analyses showed that these makers were significantly higher in the UUA1 than in the UUA3 group. CONCLUSIONS: Our findings suggest that markers of urinary interstitial inflammation and injury in CKD patients are significantly correlated with 24-h UUA and Urinary excretion of uric acid (UEUA), and those with high 24-h UUA have lower levels of these markers. Renal uric acid excretion may also reflect the inflammation and injury of renal tubules under certain conditions.

Intracellular Reactive Oxygen Species Mediate the Therapeutic Effect of Induced Pluripotent Stem Cells for Acute Kidney Injury.

AIMS: Treatment for acute kidney injury (AKI) is challenging. Induced pluripotent stem cells (iPSCs) have great therapeutic potential. This study sought to determine whether iPSCs attenuate AKI and the role of reactive oxygen species (ROS). RESULTS: We intravenously injected isogenic iPSCs into mice 2 h after renal ischemia-reperfusion injury (IRI). The cells were selectively trafficked to ischemia/reperfusion-injured kidney where they decreased kidney ROS and inflammatory cytokines and improved kidney function and morphology. Pretreating the cells with ROS inhibitors before administration decreased iPSC engraftment and abolished the protective effect of iPSCs. In contrast, pretreating iPSCs with hydrogen peroxide increased iPSC engraftment and therapeutic effect. Although the intravenously administered iPSCs trafficked to the IRI kidney, the cells did not differentiate into proximal or distal tubular epithelial cells. In vitro, the capabilities of the iPSC-released substances to promote proliferation and decrease apoptosis of renal epithelial cells were increased by ROS pretreatment of iPSCs. Moreover, pretreatment of the iPSCs with ROS inhibitor had the opposite effect. Similarly, moderate concentrations of ROS increased while ROS inhibitors decreased iPSC mobility, adhesion to the extracellular matrix, and mitochondrial metabolism. Innovation and Conclusion. iPSCs decreased renal ischemia/reperfusion injury mainly through iPSC-released substances. The therapeutic effect, mitochondrial metabolism, mobility, and kidney trafficking of iPSCs were ROS dependent.

The association of urinary uric acid excretion with ambulatory blood pressure values in patients with chronic kidney disease.

BACKGROUND: To analyze the association between hypertension and urinary uric acid excretion in patients with chronic kidney disease (CKD). METHODS: We screened 87 patients who had been admitted at the Dept of Nephrology, Huadong hospital between April 2017 to April 2019 who had completed 24-h ambulatory blood pressure monitoring and retained 24-h urine biochemical test specimens, thirty adult patients (age ≤ 65 years) with CKD 1-2 stages were recruited in the study. Pearson's correlation analysis and multiple linear regression analysis were used to study the correlation of urinary uric acid excretion with ambulatory blood pressure values and the association of morning mean diastolic pressure (mMDP), night mean diastolic pressure (nMDP) and CV of dMSP (coefficient of variation of day mean systolic pressure) with fractional excretion of uric acid (FEua) and uric acid clearance rate (Cur). Independent T test was used to compare the differences of blood pressure values in FEua1 (FEua< 6.0%) and FEua2 (FEua≥6.0%) or Cur1 (Cur < 6.2 ml/min/1.73 m2) and Cur2 (Cur ≥ 6.2 ml/min/1.73m2) groups according to the median of FEua or Cur, respectively. RESULTS: After adjusting for confounding factors, multiple linear regression analysis showed that FEua was positively associated with the mMDP and nMDP, Cur was positively associated with CV of dMSP. Levels of mMDP and nMDP in FEua1 group was lower than that in FEua2 group (both P < 0.05), level of CV of dMSP in Cur2 group were higher than that in Cur1 group (P < 0.01). CONCLUSIONS: We demonstrated that there is a positive correlation of FEua with morning and night mean diastolic pressure separately and Cur is positively related to CV of dMSP in CKD population. Monitoring the trend of urinary uric acid, may have a role in the early detection for hypertension or relative risks in the population of CKD.

AMPK alleviates high uric acid-induced Na+-K+-ATPase signaling impairment and cell injury in renal tubules.

One of the mechanisms in hyperuricemia (HUA)-induced renal tubular injury is the impairment of Na+-K+-ATPase (NKA) signaling, which further triggers inflammation, autophagy, and mitochondrial dysfunction and leads to cell injury. Here, we used RNA sequencing to screen the most likely regulators of NKA signaling and found that the liver kinase B1(LKB1)/adenosine monophosphate (AMP)-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) pathway was the most abundantly enriched pathway in HUA. AMPK is a key regulator of cell energy metabolism; hence, we examined the effect of AMPK on HUA-induced dysregulation of NKA signaling and cell injury. We first detected AMPK activation in high uric acid (UA)-stimulated proximal tubular epithelial cells (PTECs). We further found that sustained treatment with the AMPK activator 5-aminoimidazole-4-carboxamide 1-ß-d-ribofuranoside (AICAR), but not the AMPK inhibitor Compound C, significantly alleviated UA-induced reductions in NKA activity and NKA α1 subunit expression on the cell membrane by reducing NKA degradation in lysosomes; sustained AICAR treatment also significantly alleviated activation of the NKA downstream molecules Src and interleukin-1ß (IL-1ß) in PTECs. AICAR further alleviated high UA-induced apoptosis, autophagy, and mitochondrial dysfunction. Although AMPK activation by metformin did not reduce serum UA levels in hyperuricemic rats, it significantly alleviated HUA-induced renal tubular injury and NKA signaling impairment in vivo with effects similar to those of febuxostat. Our study suggests that AMPK activation may temporarily compensate for HUA-induced renal injury. Sustained AMPK activation could reduce lysosomal NKA degradation and maintain NKA function, thus alleviating NKA downstream inflammation and protecting tubular cells from high UA-induced renal tubular injury.

Low Uric Acid Indicates Risk of Incidence of Trigeminal Neuralgia.

BACKGROUND AND OBJECTIVE: Trigeminal neuralgia (TN) is a common cranial nerve disease. Uric acid (URIC), a water-soluble antioxidant discovered in human body, has been recognized in numerous recent studies to exert a crucial part in neuroprotection; however, the influence of URIC on TN remains unclear so far. This study aimed to examine the association of URIC with TN. METHODS: From January 2017 to September 2018, medical records from the newly diagnosed patients with TN at the Xinhua Hospital were retrospectively recruited and analyzed. The serum URIC, creatinine, blood urea nitrogen, and albumin levels between TN patients and normal subjects were compared through the nonparametric tests. Moreover, the relationship of URIC levels with TN was assessed using the multiple linear regression models. RESULTS: Compared with normal subjects (325.7 ±â€Š74.3 µmol/L), URIC contents were remarkably decreased in TN patients (270.2 ±â€Š75.9 µmol/L) (P < 0.05). Besides, URIC was regarded as a protective factor of TN, as verified by multivariate logistic regression models (odds ratio = 0.2, 95% confidence interval = 0.0-0.6; P < 0.05). CONCLUSION: Low URIC content is associated with the risk of incidence of TN, and appropriately increasing the URIC level may prevent TN.

Comparison and development of machine learning tools in the prediction of chronic kidney disease progression.

BACKGROUND: Urinary protein quantification is critical for assessing the severity of chronic kidney disease (CKD). However, the current procedure for determining the severity of CKD is completed through evaluating 24-h urinary protein, which is inconvenient during follow-up. OBJECTIVE: To quickly predict the severity of CKD using more easily available demographic and blood biochemical features during follow-up, we developed and compared several predictive models using statistical, machine learning and neural network approaches. METHODS: The clinical and blood biochemical results from 551 patients with proteinuria were collected. Thirteen blood-derived tests and 5 demographic features were used as non-urinary clinical variables to predict the 24-h urinary protein outcome response. Nine predictive models were established and compared, including logistic regression, Elastic Net, lasso regression, ridge regression, support vector machine, random forest, XGBoost, neural network and k-nearest neighbor. The AU-ROC, sensitivity (recall), specificity, accuracy, log-loss and precision of each of the models were evaluated. The effect sizes of each variable were analysed and ranked. RESULTS: The linear models including Elastic Net, lasso regression, ridge regression and logistic regression showed the highest overall predictive power, with an average AUC and a precision above 0.87 and 0.8, respectively. Logistic regression ranked first, reaching an AUC of 0.873, with a sensitivity and specificity of 0.83 and 0.82, respectively. The model with the highest sensitivity was Elastic Net (0.85), while XGBoost showed the highest specificity (0.83). In the effect size analyses, we identified that ALB, Scr, TG, LDL and EGFR had important impacts on the predictability of the models, while other predictors such as CRP, HDL and SNA were less important. CONCLUSIONS: Blood-derived tests could be applied as non-urinary predictors during outpatient follow-up. Features in routine blood tests, including ALB, Scr, TG, LDL and EGFR levels, showed predictive ability for CKD severity. The developed online tool can facilitate the prediction of proteinuria progress during follow-up in clinical practice.