Causal role of immune cells in aplastic anemia: Mendelian randomization (MR) study.

Prior research has identified associations between immune cells and aplastic anaemia (AA); however, the causal relationships between them have not been conclusively established. A two-sample Mendelian randomisation analysis was conducted to investigate the causal link between 731 immune cell signatures and AA risk using publicly available genetic data. Four types of immune signatures, including relative cell, absolute cell (AC), median fluorescence intensities and morphological parameters, were considered sensitivity analyses were also performed to verify the robustness of the results and assess potential issues such as heterogeneity and horizontal pleiotropy. Following multiple test adjustments using the False Discovery Rate (FDR) method, no statistically significant impact of any immunophenotype on AA was observed. However, twelve immunophenotypes exhibited a significant correlation with AA without FDR correction (p of IVW < 0.01), of which eight were harmful to AA: CD127- CD8br %T cell (Treg panel), CD25 on IgD + CD38dim (B cell panel), CD38 on naive-mature B cell (B cell panel), CD39 + resting Treg % CD4 Treg (Treg panel), CD39 + secreting Treg AC (Treg panel), CD8 on CD28 + CD45RA- CD8br (Treg panel), HLA DR + NK AC (TBNK panel), Naive DN (CD4-CD8-) AC (Maturation stages of T cell panel); and four were protective to AA: CD86 on CD62L + myeloid DC (cDC panel), DC AC (cDC panel), DN (CD4-CD8-) NKT %T cell (TBNK panel), and TD CD4 + AC (Maturation stages of T cell panel). The results of this study demonstrate a close link between immune cells and AA by genetic means, thereby improving the current understanding of the interaction between immune cells and AA risk and providing guidance for future clinical research.

Cathepsin S (CTSS) in IgA nephropathy: an exploratory study on its role as a potential diagnostic biomarker and therapeutic target.

Introduction: IgA nephropathy (IgAN), a prevalent form of glomerulonephritis globally, exhibits complex pathogenesis. Cathepsins, cysteine proteases within lysosomes, are implicated in various physiological and pathological processes, including renal conditions. Prior observational studies have suggested a potential link between cathepsins and IgAN, yet the precise causal relationship remains unclear. Methods: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning. Results: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS. Conclusion: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.

Nanocluster/metal-organic framework nanosheet-based confined ECL enhancement biosensor for the extracellular vesicle detection.

Gastric cancer (GC) was one of the most common cancers with high mortality. The detection of GC peritoneal metastasis had important significance. In this work, we have developed the novel electrochemiluminescence (ECL) biosensor to detect microRNA in GC extracellular vesicle (EV). Firstly, in situ growth of Cu nanocluster (Cu NC) on the metal-organic frameworks (MOFs) nanosheet was achieved successfully. Due to the confinement effect, Cu NCs in the porous structure of Zn MOF possessed the high quantum yield and good stability. Meanwhile, Zn MOF provided good electrochemical activity for the ECL reaction. Furthermore, the nanosized MOFs did not only act as sensing platform to load Cu NCs and link biomolecules, but also reduce steric hindrance effect for biomolecular recognition. Additionally, Au NPs/MXene and phospholipid layer were prepared and modified on the electrode, which can regulate electron transfer and improve the target recognition efficiency. The Cu NCs/Zn MOF nanosheet-based ECL sensor was employed to detect miRNA-421 from 1 fM to 1 nM with a detection limit of 0.5 fM. Finally, extracellular vesicles form clinic GC patient ascites were extracted and analyzed. The results showed that the constructed biosensor can be used for the GC peritoneal metastasis diagnosis.

Renal interferon-inducible protein 16 expression is associated with disease activity and prognosis in lupus nephritis.

BACKGROUND: Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus (SLE). However, the current management of LN remains unsatisfactory due to sneaky symptoms during early stages and lack of reliable predictors of disease progression. METHODS: Bioinformatics and machine learning algorithms were initially used to explore the potential biomarkers for LN development. Identified biomarker expression was evaluated by immunohistochemistry (IHC) and multiplex immunofluorescence (IF) in 104 LN patients, 12 diabetic kidney disease (DKD) patients, 12 minimal change disease (MCD) patients, 12 IgA nephropathy (IgAN) patients and 14 normal controls (NC). The association of biomarker expression with clinicopathologic indices and prognosis was analyzed. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were utilized to explore potential mechanisms. RESULTS: Interferon-inducible protein 16 (IFI16) was identified as a potential biomarker for LN. IFI16 was highly expressed in the kidneys of LN patients compared to those with MCD, DKD, IgAN or NC. IFI16 co-localized with certain renal and inflammatory cells. Glomerular IFI16 expression was correlated with pathological activity indices of LN, while tubulointerstitial IFI16 expression was correlated with pathological chronicity indices. Renal IFI16 expression was positively associated with systemic lupus erythematosus disease activity index (SLEDAI) and serum creatinine while negatively related to baseline eGFR and serum complement C3. Additionally, higher IFI16 expression was closely related to poorer prognosis of LN patients. GSEA and GSVA suggested that IFI16 expression was involved in adaptive immune-related processes of LN. CONCLUSION: Renal IFI16 expression is a potential biomarker for disease activity and clinical prognosis in LN patients. Renal IFI16 levels may be used to shed light on predicting the renal response and develop precise therapy for LN.

[Simulation design and experimental study of magnetic stimulation coil for robot pigeon].

To explore the feasibility of applying magnetic stimulation technology to the movement control of animal robots, the influence of coil radius, number of turns and other factors on the intensity, depth and focus of magnetic stimulation was simulated and analyzed for robot pigeons. The coil design scheme was proposed. The coil was placed on the head and one of the legs of the pigeon, and the leg electromyography (EMG) was recorded when magnetic stimulation was performed. Results showed that the EMG was significantly strengthened during magnetic stimulation. With the reduction of the output frequency of the magnetic stimulation system, the output current was increased and the EMG was enhanced accordingly. Compared with the brain magnetic stimulation, sciatic nerve stimulation produced a more significant EMG enhancement response. This indicated that the magnetic stimulation system could effectively modulate the functions of brain and peripheral nerves by driving the coil. This study provides theoretical and experimental guidance for the subsequent optimization and improvement of practical coils, and lays a preliminary theoretical and experimental foundation for the implementation of magnetic stimulation motion control of animal robots.

Effects of Selenium on Chronic Kidney Disease: A Mendelian Randomization Study.

BACKGROUND: Previous observational studies have shown that there is a controversial association between selenium levels and chronic kidney disease (CKD). Our aim was to assess the causal relationship between selenium levels and CKD using Mendelian randomization (MR) analysis. METHODS: We used the two-sample Mendelian randomization (MR) method to analyze the causal role of selenium levels on CKD risk. The variants associated with selenium levels were extracted from a large genome-wide association study (GWAS) meta-analysis of circulating selenium levels (n = 5477) and toenail selenium levels (n = 4162) in the European population. Outcome data were from the largest GWAS meta-analysis of European-ancestry participants for kidney function to date. Inverse variance weighted (IVW) method was used as the main analysis and a series of sensitivity analyses were carried out to detect potential violations of MR assumptions. RESULTS: The MR analysis results indicate that the genetically predicted selenium levels were associated with decreased estimated glomerular filtration (eGFR) (effect = -0.0042, 95% confidence interval [CI]: -0.0053-0.0031, p = 2.186 × 10-13) and increased blood urea nitrogen (BUN) (effect = 0.0029, 95% confidence interval [CI]: 0.0006-0.0052, p = 0.0136) with no pleiotropy detected. CONCLUSIONS: The MR study indicated that an increased level of selenium is a causative factor for kidney function impairment.

Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in maintenance dialysis: a meta-analysis.

BACKGROUND: Anaemia is a common complication of end-stage renal disease (ESRD) that relies on dialysis. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) is a new class of small-molecule oral drugs for the treatment of anaemia in chronic kidney disease. They demonstrate several advantages over traditional exogenous erythropoietin (EPO). We conducted a meta-analysis of studies that compared the efficacy of HIF-PHI in erythropoiesis and iron metabolism, and its safety with EPO in maintenance dialysis patients. METHODS: A sensitive search strategy in the PubMed, EMBASE and Cochrane databases identified all citations for randomised controlled trials (RCTs) comparing HIF-PHI agents with EPO/placebo through December 2021. RESULTS: Fourteen RCTs were identified, which included 2738 patients. No statistical difference was found in haemoglobin increase (p = 0.37) between HIF-PHI treatment and EPO using the random-effects model. HIF-PHI administration upregulated transferrin (MD 36.12, 95% CI 27.04-45.20) and soluble transferrin receptors (sTfR) (MD 1.28, 95% CI 0.44-2.13), but did not statistically reduce hepcidin level (p = 0.37). Total and LDL-cholestrol levels were suppressed by HIF-PHI (MD - 0.99, 95% CI - 1.34 to - 0.63) (MD - 0.99, 95% CI - 1.34 to - 0.64), while triglyceride (TG) was not different between HIF-PHI and EPO (p = 0.74). The total incident rates of treatment-emergent adverse events (TEAE) (p = 0.20) from HIF-PHI treatment were not different from those of erythropoietin, while the treatment-emergent serious adverse events (TSAE) (p = 0.02) were higher in the HIF-PHI group than those in the EPO controls with the fixed-effect model. CONCLUSION: HIF-PHI could effectively upregulate and maintain haemoglobin levels in patients with anaemia receiving maintenance dialysis. Furthermore, HIF-PHI could elevate iron metabolism activity and utility without inducing treatment-associated serious adverse events. Robust data from larger RCTs with longer treatment duration and follow-up are needed.

Krill Oil Turns Off TGF-ß1 Profibrotic Signaling in the Prevention of Diabetic Nephropathy.

Diabetic nephropathy (DN), a severe microvascular complication of diabetes mellitus (DM), results in high mortality due to the lack of effective interventions. The current study investigated the preventive effect of krill oil (KO) on DN using a type 2 DM mouse model induced by streptozotocin and high-fat diet for 24 weeks. The diabetic mice developed albuminuria, mesangial matrix accumulation, glomerular hypertrophy, and fibrosis formation, with an increase in renal proinflammatory, oxidative and profibrotic gene expression. KO significantly prevented these effects but did not improve hyperglycemia and glucose intolerance. In high-glucose-treated mesangial cells (MCs), KO preferably modulated TGF-ß1 signaling as revealed by RNA-sequencing. In TGF-ß1-treated MCs, KO abolished SMAD2/3 phosphorylation and nuclear translocation and activated Smad7 gene expression. The action of KO on the SMADs was confirmed in the diabetic kidneys. Therefore, KO may prevent DN predominantly by suppressing the TGF-ß1 signaling pathway.

Blood HDAC4 Variation Links With Disease Activity and Response to Tumor Necrosis Factor Inhibitor and Regulates CD4+ T Cell Differentiation in Ankylosing Spondylitis.

Purpose: Histone deacetylase 4 (HDAC4) regulates the progression of autoimmune diseases. This study aimed to further investigate the correlation between HDAC4 and Th cells, inflammation, disease activity, and treatment response in patients with ankylosing spondylitis (AS). Methods: A total of 132 active patients with AS were enrolled, of whom 54 patients received TNF inhibitor (TNFi) and 78 patients received NSAID. Serum HDAC4 was measured by ELISA in patients with AS before treatment (W0) and at week (W)4, W8, and W12 after treatment. Meanwhile, serum HDAC4 was detected in 30 patients with osteoarthritis and in 30 healthy controls (HCs) by ELISA. Besides, naïve CD4+ T cells from patients with AS were isolated, followed by modulation of HDAC4 and then polarization toward Th1, Th2, and Th17. Results: Histone deacetylase 4 was reduced in patients with AS compared with HCs and patients with osteoarthritis (both P < 0.01). In patients with AS, HDAC4 was negatively correlated with TNF (P < 0.001), IL-1ß (P = 0.003), Th17 proportion (P = 0.008), C-reactive protein (P < 0.001), and ASDAS (P = 0.038), but not with IL-6, Th1 proportion, or other characteristics. Meanwhile, HDAC4 increased from W0 to W12 (P < 0.001); HDAC4 at W8 (P = 0.014) and W12 (P = 0.006) was raised in ASAS40-response patients than ASAS40-non-response patients; further subgroup analysis showed that HDAC4 at W12 was higher in ASAS40-response patients than ASAS40-non-response patients (P = 0.016) in the TNFi-treated group, but not in the NSAID-treated group. In addition, HDAC4 negatively regulated the polarization of naïve CD4+ T cells toward Th17 (P < 0.01), but not Th1 or Th2. Conclusion: Histone deacetylase 4 is associated with lower inflammation, and the disease activity negatively regulates Th17 polarization, whose increment after treatment reflects favorable outcomes in patients with AS.

The common risk factors for progression and mortality in COVID-19 patients: a meta-analysis.

Coronavirus disease 2019 (COVID-19), defined by the World Health Organization (WHO), has affected more than 50 million patients worldwide and caused a global public health emergency. Therefore, there is a recognized need to identify risk factors for COVID-19 severity and mortality. A systematic search of electronic databases (PubMed, Embase and Cochrane Library) for studies published before September 29, 2020, was performed. Studies that investigated risk factors for progression and mortality in COVID-19 patients were included. A total 344,431 participants from 34 studies were included in this meta-analysis. Regarding comorbidities, cerebrovascular disease (CVD), chronic kidney disease (CKD), coronary heart disease (CHD), and malignancy were associated with an increased risk of progression and mortality in COVID-19 patients. Regarding clinical manifestations, sputum production was associated with a dramatically increased risk of progression and mortality. Hemoptysis was a risk factor for death in COVID-19 patients. In laboratory examinations, increased neutrophil count, decreased lymphocyte count, decreased platelet count, increased C-reactive protein (CRP), coinfection with bacteria or fungi, increased alanine aminotransferase (ALT) and creatine kinase (CK), increased N-terminal pronatriuretic peptide (NT-proBNP), and bilateral pneumonia in CT/X-ray were significantly more frequent in the severe group compared with the non-severe group. Moreover, the proportion of patients with increased CRP and total bilirubin (TBIL) was also significantly higher in the deceased group than in the survival group. CVD, CKD, sputum production, increased neutrophil count, decreased lymphocyte count, decreased platelet count, increased CRP, coinfection with bacteria or fungi, increased ALT and CK, increased NT-proBNP, and bilateral pneumonia in CT/X-ray were associated with an increased risk of progression in COVID-19 patients. Moreover, the proportion of patients with increased sputum production, hemoptysis, CRP and TBIL was also significantly higher in the deceased group.

Establishment of a novel risk score model by comprehensively analyzing the immunogen database of bladder cancer to indicate clinical significance and predict prognosis.

BACKGROUND: Bladder cancer (BCa) has the highest incidence of aggressive malignant tumors in the urogenital system and is the ninth most common cancer worldwide. Immune function-related genes (IFRGs), which are plentiful in immune cells and the immune microenvironment (IME), have the potential to assess prognosis and predict the efficacy of immunotherapy. A complete and significant immunogenomic analysis based on abundant BCa genetic samples from The Cancer Genome Atlas (TCGA) will provide insight into the field. RESULTS: A total of 57 differentially expressed IFRGs were significantly associated with the clinical outcomes of patients with BCa. Functional enrichment analysis showed that these genes actively participated in the KEGG pathway of human cytomegalovirus infection. Based on the IFRGs (CALR, MMP9, PAEP, RBP7, STAT1, CACYBP, ANHAK, RAC3, SLIT2, EDNRA, IGF1, NAMPT, NTF3, PPY, ADRB2 and SH3BP2), the risk scores were calculated to predict survival and reveal the relationships with age, sex, grade, staging, T-stage, N-stage, and M-stage. Interestingly, IFRG-based risk scores (IRRSs) reflected the infiltration of several types of immune cells. The expression of CACYBP was more significant in grade 3, T3 and T4 stages than in earlier grades and T-stages. CONCLUSION: Our results highlighted some sIFRGs with remarkable clinical relevance, showed the driving factors of the immune repertoire, and illustrated the significance of IFRG-based individual immune features in the identification, monitoring, and prognosis of patients with BCa. METHODS: Based on the TCGA dataset, we integrated the expression profiles of IFRGs and overall survival (OS) in 430 patients with BCa. Differentially expressed IFRGs and survival-related IFRGs (sIFRGs) were highlighted by calculating the difference algorithm and COX regression analysis in patients with BCa. Based on computational biology, the potential molecular mechanisms and characteristics of these IFRGs were also explored. Using multivariate Cox analysis, new risk scores based on immune-related genes were developed. The expression of CACYBP was verified by qPCR, western blot and immunohistochemistry. The relations between CACYBP and clinical features were proven by immunohistochemistry.

The Role of Akt2 in the Protective Effect of Fenofibrate against Diabetic Nephropathy.

Fenofibrate (FF) protects against diabetic nephropathy (DN) in type 1 diabetic (T1D) mice by upregulating the expression of fibroblast growth factor 21 (FGF21), leading to the activation of the Akt-mediated Nrf2 antioxidant pathways. Here, we examined which isoforms of Akt contribute to FF activation of FGF21-mediated renal protection by examining the phosphorylation and expression of three isoforms, Akt1, Akt2, and Akt3. T1D induced by a single intraperitoneal dose of streptozotocin (STZ) resulted in reduced phosphorylation of one isoform, Akt2, but FF treatment increased renal Akt2 phosphorylation in these and normal mice, suggesting a potential and specific role for renal Akt2 in FF protection against T1D. This was further confirmed using in vitro cultured HK-2 human kidney tubule cells exposed to high glucose (HG) with siRNA silencing of the Akt2 gene and STZ-induced diabetic Akt2-knockout mice with and without 3-month FF treatment. In normal HK-2 cells exposed to HG for 24 hours, FF completely prevented cell death, reduced total Akt expression and glycogen synthase kinase (GSK)-3ß phosphorylation, increased nuclear accumulation of Fyn, and reduced nuclear Nrf2 levels. These positive effects of FF were partially abolished by silencing Akt2 expression. Similarly, FF abolished T1D-induced renal oxidative stress, inflammation, and renal dysfunction in wild-type mice, but was only partially effective in Akt2-KO mice. Furthermore, FF treatment stimulated phosphorylation of AMPKα, an important lipid metabolism mediator, which in parallel with Akt2 plays an important role in FF protection against HG-induced HK-2 cells oxidative stress and damage. These results suggest that FF protects against DN through FGF21 to activate both Akt2/GSK-3ß/Fyn/Nrf2 antioxidants and the AMPK pathway. Therefore, FF could be repurposed for the prevention of DN in T1D patients.

MicroRNA-200a improves diabetic endothelial dysfunction by targeting KEAP1/NRF2.

Over a half of the diabetic individuals develop macrovascular complications that cause high mortality. Oxidative stress (OS) promotes endothelial dysfunction (ED) which is a critical early step toward diabetic macrovascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system and combats diabetes-induced OS. Previously, we found that impaired NRF2 antioxidant signaling contributed to diabetes-induced endothelial OS and dysfunction in mice. The present study has investigated the effect of microRNA-200a (miR-200a) on NRF2 signaling and diabetic ED. In aortic endothelial cells (ECs) isolated from C57BL/6 wild-type (WT) mice, high glucose (HG) reduced miR-200a levels and increased the expression of kelch-like ECH-associated protein 1 (Keap1) - a target of miR-200a and a negative regulator of NRF2. This led to the inactivation of NRF2 signaling and exacerbation of OS and inflammation. miR-200a mimic (miR-200a-M) or inhibitor modulated KEAP1/NRF2 antioxidant signaling and manipulated OS and inflammation under HG conditions. These effects were completely abolished by knockdown of Keap1, indicating that Keap1 mRNA is a major target of miR-200a. Moreover, the protective effect of miR-200a-M was completely abrogated in aortic ECs isolated from C57BL/6 Nrf2 knockout (KO) mice, demonstrating that NRF2 is required for miR-200a's actions. In vivo, miR-200a-M inhibited aortic Keap1 expression, activated NRF2 signaling, and attenuated hyperglycemia-induced OS, inflammation and ED in the WT, but not Nrf2 KO, mice. Therefore, the present study has uncovered miR-200a/KEAP1/NRF2 signaling that controls aortic endothelial antioxidant capacity, which protects against diabetic ED.

Integrative Informatics Analysis of Transcriptome and Identification of Interacted Genes in the Glomeruli and Tubules in CKD.

Chronic kidney disease (CKD) is a complex disease in which the renal function is compromised chronically. Many studies have indicated the crosstalk between the tubule and the glomerulus in CKD progression. However, our understanding of the interaction of tubular and glomerular injury remains incomplete. In this study, we applied a meta-analysis approach on the transcriptome of the tubules and glomeruli of CKD patients to identify differentially expressed genes (DEGs) signature. Functional analysis of pathways and Gene Ontology found that tubular DEGs were mainly involved in cell assembly and remodeling, glomerular DEGs in cell proliferation and apoptosis, and overlapping DEGs mainly in immune response. Correlation analysis was performed to identify the associated DEGs in the tubules and glomeruli. Secreted protein comparison and verification experiments indicated that WFDC2 from the tubule could downregulate PEX19 mRNA and protein levels at the glomeruli in diabetic kidney disease (DKD). This study revealed the distinctive pathways of the tubules and glomeruli and identified interacted genes during CKD progression.

MicroRNA-544 attenuates diabetic renal injury via suppressing glomerulosclerosis and inflammation by targeting FASN.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Accumulating evidence shows that microRNAs play important roles in diabetic kidney. However, the potential role of MicroRNA-544 (miR-544) in DN remains unclear. In this study, we explored the role of miR-544 on inflammation and fibrosis in diabetic kidney using db/db mice. Renal expression of miR-544 was decreased in mice, companied by increased the expression of FASN. The dual luciferase assay confirmed FASN as a direct target of miR-544. Over-expression of miR-544 significantly ameliorated renal injury, mesangial matrix and renal fibrosis. In addition, over-expression of miR-544 significantly attenuated inflammatory cells infiltration and IL-1, IL-6, TNF- and iNOS production in DN. Furthermore, miR-544 over-expression inhibited the activation of NF-kB signal pathway in DN. In conclusion, our finding demonstrated that miR-544 attenuates diabetic renal injury via suppressing glomerulosclerosis and inflammation by targeting FASN, suggesting that miR-544 might have therapeutic potential for the treatment of DN.

Prophylactic atorvastatin prior to intra-arterial administration of iodinated contrast media for prevention of contrast-induced acute kidney injury: A meta-analysis of randomized trial data
.

BACKGROUND: The efficacy of high-dose atorvastatin pretreatment in reducing the incidence of contrast-induced nephropathy in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) has been examined in some randomized studies. However, the results across the trials remain controversial. OBJECTIVE: This study sought to perform a meta-analysis to evaluate the effect of high-dose atorvastatin in the prevention of contrast-induced nephropathy (CIN) while undergoing CAG or PCI. MATERIALS AND METHODS: Comprehensive literature searches for randomized controlled trials (RCTs) comparing high-dose atorvastatin vs. low-dose statin or placebo pretreatment for prevention of contrast-induced acute kidney injury in patients undergoing CAG were performed using PubMed, Embase, and the Cochrane library updated to June 2017. The primary outcome was the incidence of CIN. RESULTS: A total of 11 RCTs were included in this analysis. The high-dose atorvastatin treatment can significantly reduce the incidence of CIN (OR 0.46, 95% CI 0.35 - 0.62, p < 0.00001). The benefit was consistent in comparison with the low-dose group (OR 0.41, 95% CI 0.25 - 0.66, p = 0.0003) and the placebo group (OR 0.50, 95% CI 0.26 - 0.98, p = 0.04). CONCLUSION: Our study demonstrates that high-dose statin pretreatment shows a benefit specifically in reducing the incidence of contrast-induced acute kidney injury in patients undergoing CAG, especially compared with low-dose statin pretreatment.

Overexpression of the long non-coding RNA Oprm1 alleviates apoptosis from cerebral ischemia-reperfusion injury through the Oprm1/miR-155/GATA3 axis.

Numerous differentially expressed long non-coding RNAs (lncRNAs) have been identified in cerebral ischemia-reperfusion (I/R) injury using RNA-Seq analysis. However, little is known about whether and how lncRNAs are involved in cerebral I/R injury. In this study, we investigated the function of the lncRNA Oprm1 in cerebral I/R injury and explored the underlying mechanism. An oxygen-glucose deprivation model in N2a cells was utilized to mimic cerebral I/R injury in vitro. Trypan blue staining, terminal deoxytransferase-mediated dUTP-biotin nick end labelling and caspase-3 were measured to evaluate apoptosis. Middle cerebral artery occlusion was performed in mice to evaluate the function of lncRNA Oprm1 in vivo. Real-time PCR and western blotting were used to measure the expression levels of lncRNA Opmr1, caspase-3, miR-155, GATA binding protein 3 (GATA3) and nuclear factor (NF)-κB. lncRNA Oprm1 was mainly located in the cytoplasm. Overexpression of lncRNA Oprm1 alleviated the apoptosis induced by oxygen-glucose deprivation and significantly reduced cleaved caspase-3 levels. Infarct size was distinctly decreased in the lncRNA Oprm1-overexpression group. The neurological score was also improved. Our findings showed that the lncRNA Oprm1/miR-155/GATA3 axis plays an important role in cerebral I/R injury. lncRNA Oprm1 may attenuate cerebral injury through the NF-κB pathway. lncRNA Oprm1 may serve as a potential target for new therapeutic interventions in patients with ischemic stroke.

Role of microRNA-15a-5p in the atherosclerotic inflammatory response and arterial injury improvement of diabetic by targeting FASN.

The present study aims to investigate the mechanism of miR-15a-5p in the atherosclerotic (AS) inflammatory response and arterial injury improvement in diabetic rats by regulating fatty acid synthase (FASN). Initially, bioinformatics tools were applied to evaluate miRNAs and genes correlating with AS, and the target relation between miRNAs and FASN was measured using the Dual-Luciferase Reporter Assay. Subsequently the diabetic AS rat model was established and the surviving rats were divided into: negative control (NC), miR-15a-5p mimic, miR-15a-5p inhibitor, sh-FASN and miR-15a-5p + sh-FASN groups. Then a series of experiments were performed to examine the degree of AS in each group. The results revealed that compared with the NC group, the expressions of C-reactive protein (CRP), interleukin 6 (IL-6), intercellular cell adhesion molecule-1 (ICAM1) in rat arterial tissue, as well as the levels of low-density lipoprotein cholesterol (LDL-C), blood glucose (BG), triglycerides (TG), total cholesterol (TC) and Homocysteine (Hcy) in rat serum, were increased after inhibiting miR-15a-5p, while the level of high-density lipoprotein cholesterol (HDL-C) was decreased and the fat storage area was enlarged after this treatment (P<0.05). In the miR-15a-5p mimic and sh-FASN groups, serum HDL-C levels were increased and the fat storage areas in arteries were reduced. The levels of CRP, IL-6, ICAM1 in rat arterial tissue, along with the levels of LDL-C, BG, TG, TC and Hcy in rat serum, were decreased (P<0.05). Hematoxylin and Eosin (HE) staining and transmission electron microscopy (TEM) results showed AS lesions to be apparent in the arteries of rats in both the NC and miR-15a-5p inhibitor groups, but that in miR-15a-5p and sh-FASN group were improved, the miR-15a-5p mimic + sh-FASN group showed the most obvious improvement. Taken together, miR-15a-5p alleviates the inflammation response and arterial injury in diabetic AS rats by targeting FASN.

IgA nephropathy associated with erythrodermic psoriasis: A case report.

RATIONALE: Cases about IgAN associated with EP are rare and the pathogenesis is poorly understood. We reported a 74-year-old Chinese male who suffered the IgAN and EP at the same time and explored a possible pathophysiologic link and points toward the possible pathogenesis. PATIENT CONCERNS: The patient complained deteriorating symptoms (erythrodermia, skin pruritus, and pain) of psoriasis and obvious pitting edema on his legs. DIAGNOSIS: The patient was diagnosed as IgAN and EP concurrently according to medical history, physical examination, laboratory test, and pathology. INTERVENTIONS: Intravenous dexamethasone (5 mg/day) and oral ciclosporin (200 mg twice a day). OUTCOMES: The patient's symptoms of psoriasis and IgA nephropathy improved obviously after 11-day treatment and discharged from the hospital. LESSONS: IgAN should be considered when the patient is diagnosed as EP. The combination of dexamethasone and ciclosporin may be effective option for patients with IgAN and EP concurrently.

P53/NRF2 mediates SIRT1's protective effect on diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of end stage renal disease, posing a severe threat to public health. Previous studies reported the protective role of sirtuin 1 (SIRT1) in DN, encouraging the investigation of more potent and specific SIRT1 activators. SRT2104 is a novel, first-in-class, highly selective small-molecule activator of SIRT1, with its effect and mechanism unknown on DN. To this end, streptozotocin-induced C57BL/6 wild-type (WT) diabetic mice were treated with SRT2104, for 24 weeks. To determine whether SRT2104 acted through inhibition of P53 - a substrate of SIRT1, the P53 activator nutlin3a was administered to the WT diabetic mice in the presence of SRT2104. In order to test whether nuclear factor erythroid 2-related factor 2 (NRF2) - the master of cellular antioxidants - mediated SIRT1 and P53's actions, WT and Nrf2 gene knockout (KO) diabetic mice were treated with SRT2104 or the P53 inhibitor pifithrin-α (PFT-α). In the WT mice, SRT2104 enhanced renal SIRT1 expression and activity, deacetylated P53, and activated NRF2 antioxidant signaling, providing remarkable protection against the DM-induced renal oxidative stress, inflammation, fibrosis, glomerular remodeling and albuminuria. These effects were completely abolished in the presence of nutlin3a. Deletion of the Nrf2 gene completely abrogated the efficacies of SRT2104 and PFT-α in elevating antioxidants and ameliorating DN, despite their abilities to activate SIRT1 and inhibit P53 in the Nrf2 KO mice. The present study reports the beneficial effects of SRT2104 on DN, uncovering a SIRT1/P53/NRF2 pathway that modulates the pathogenesis of DN.