Hospitalized patients received furosemide undergoing acute kidney injury: the risk and prediction tool.

PURPOSE: Furosemide, a frequently prescribed diuretic for managing congestive heart failure and edema, remains a topic of debate regarding its potential risk of inducing acute kidney injury (AKI) in patients. Consequently, this study aims to examine the occurrence of hospital-acquired AKI (HA-AKI) in hospitalized patients who are administered furosemide and to investigate potential risk factors associated with this outcome. METHODS: This study encompassed a cohort of 22374 hospitalized patients who either received furosemide treatment or not from June 1, 2012, to December 31, 2017. Propensity score matching was employed to establish comparability between the two groups regarding covariates. Subsequently, a nomogram was constructed to predict the probability of AKI occurrence among patients who underwent furosemide treatment. RESULTS: The regression analysis identified the single-day total dose of furosemide as the most significant factor for AKI, followed by ICU administration, estimated glomerular filtration rate, antibiotic, statin, NSAIDs, ß-blockers, proton pump inhibitor, chronic kidney disease, and 7 other indicators. Subgroup analysis revealed a synergistic effect of furosemide with surgical operation, previous treatment with ß-blockers, ACEI/ARB and antibiotics, leading to an increased risk of AKI when used in combination. Subsequently, a visually represented prognostic nomogram was developed to predict AKI occurrence in furosemide users. The predictive accuracy of the nomogram was assessed through calibration analyses, demonstrating an excellent agreement between the nomogram predictions and the actual likelihood of AKI, with a probability of 77.40%. CONCLUSIONS: Careful consideration of factors such as dosage, concurrent medication use, and renal function of the patient is necessary for clinical practice when using furosemide. Our practical prognostic model for HA-AKI associated with furosemide use can be utilized to assist clinicians in making informed decisions about patient care and treatment.

Hexarelin alleviates apoptosis on ischemic acute kidney injury via MDM2/p53 pathway.

INTRODUCTION: Hexarelin exhibits significant protection against organ injury in models of ischemia/reperfusion (I/R)-induced injury (IRI). Nevertheless, the impact of Hexarelin on acute kidney injury (AKI) and its underlying mechanism remains unclear. In this study, we investigated the therapeutic potential of Hexarelin in I/R-induced AKI and elucidated its molecular mechanisms. METHODS: We assessed the protective effects of Hexarelin through both in vivo and in vitro experiments. In the I/R-induced AKI model, rats were pretreated with Hexarelin at 100 µg/kg/d for 7 days before being sacrificed 24 h post-IRI. Subsequently, kidney function, histology, and apoptosis were assessed. In vitro, hypoxia/reoxygenation (H/R)-induced HK-2 cell model was used to investigate the impact of Hexarelin on apoptosis in HK-2 cells. Then, we employed molecular docking using a pharmmapper server and autodock software to identify potential target proteins of Hexarelin. RESULTS: In this study, rats subjected to I/R developed severe kidney injury characterized by tubular necrosis, tubular dilatation, increased serum creatinine levels, and cell apoptosis. However, pretreatment with Hexarelin exhibited a protective effect by mitigating post-ischemic kidney pathological changes, improving renal function, and inhibiting apoptosis. This was achieved through the downregulation of conventional apoptosis-related genes, such as Caspase-3, Bax and Bad, and the upregulation of the anti-apoptotic protein Bcl-2. Consistent with the in vivo results, Hexarelin also reduced cell apoptosis in post-H/R HK-2 cells. Furthermore, our analysis using GSEA confirmed the essential role of the apoptosis pathway in I/R-induced AKI. Molecular docking revealed a strong binding affinity between Hexarelin and MDM2, suggesting the potential mechanism of Hexarelin's anti-apoptosis effect at least partially through its interaction with MDM2, a well-known negative regulator of apoptosis-related protein that of p53. To validate these findings, we evaluated the relative expression of MDM2 and p53 in I/R-induced AKI with or without Hexarelin pre-administration and observed a significant suppression of MDM2 and p53 by Hexarelin in both in vivo and in vitro experiments. CONCLUSION: Collectively, Hexarelin was identified as a promising medication in protecting apoptosis against I/R-induced AKI.

Calycosin attenuates renal ischemia/reperfusion injury by suppressing NF-κB mediated inflammation via PPARγ/EGR1 pathway.

Renal ischemia reperfusion injury (IRI) is a leading and common cause of acute kidney injury (AKI), and inflammation is a critical factor in ischemic AKI progression. Calycosin (CAL), a major active component of Radix astragali, has been reported to have anti-inflammatory effect in multiple organs. However, whether CAL can alleviate renal IRI and its mechanism remain uncertain. In the present study, a renal IRI model is established by bilateral renal pedicles occlusion for 35 min in male C57BL/6 mice, and the effect of CAL on renal IRI is measured by serum creatinine and pathohistological assay. Hypoxia/reoxygenation (H/R) stimulated human renal tubular epithelial cells HK-2 were applied to explore the regulatory mechanisms of CAL. Luciferase reporter assay and molecular docking were applied to identify the CAL's target protein and pathway. In the mice with renal IRI, CAL dose dependently alleviated the renal injury and decreased nuclear factor kappa B (NF-κB) mediated inflammatory response. Bioinformatics analysis and experiments showed that early growth response 1 (EGR1) increased in mice with renal IRI and promoted NF-κB mediated inflammatory processes, and CAL dose-dependably reduced EGR1. Through JASPAR database and luciferase reporter assay, peroxisome proliferator-activated receptor γ (PPARγ) was predicted to be a transcription factor of EGR1 and repressed the expression of EGR1 in renal tubular epithelial cells. CAL could increase PPARγ in a dose dependent manner in mice with renal IRI and molecular docking predicted CAL could bind stably to PPARγ. In HK-2 cells after H/R, CAL increased PPARγ, decreased EGR1, and inhibited NF-κB mediated inflammatory response. However, PPARγ knockdown by siRNA transfection abrogated the anti-inflammation therapeutic effect of CAL. CAL produced a protective effect on renal IRI by attenuating NF-κB mediated inflammatory response via PPARγ/EGR1 pathway.

Tilianin Reduces Apoptosis via the ERK/EGR1/BCL2L1 Pathway in Ischemia/Reperfusion-Induced Acute Kidney Injury Mice.

Background: Acute kidney injury (AKI) is a common syndrome impacting about 13.3 million patients per year. Tilianin has been reported to alleviate myocardial ischemia/reperfusion (I/R) injury, while its effect on AKI is unknown; thus, this study aimed to explore if tilianin protects I/R-induced AKI and the underlying mechanisms. Methods: The microarray dataset GSE52004 was downloaded from GEO DataSets (Gene Expression Omnibus). Differential expression analysis and gene-set enrichment analysis (GSEA) were performed by R software to identify apoptosis pathway-related genes. Then, RcisTarget was applied to identify the transcription factor (TF) related to apoptosis. The STRING database was used to construct a protein-protein interaction (PPI) network. Cytoscape software visualized PPI networks, and hub TFs were selected via cytoHubba. AutoDock was used for molecular docking of tilianin and hub gene-encoded proteins. The expression levels of hub genes were assayed and visualized by quantitative real-time PCR, Western blotting, and immunohistochemistry by establishing I/R-induced AKI mouse models. Results: Bioinformatics analysis showed that 34 genes, including FOS, ATF4, and Gadd45g, were involved in the apoptosis pathway. In total, seven hub TFs might play important roles in tilianin-regulating apoptosis pathways. In in vivo, tilianin improved kidney function and reduced the number of TUNEL-positive renal tubular epithelial cells (RTECs) after I/R-induced AKI. Tilianin reduced the activation of the ERK pathway and then downregulated the expression of EGR1. This further ameliorated the expression of anti-apoptotic genes such as BCL2L1 and BCL2, reduced pro-apoptotic genes such as BAD, BAX, and caspase-3, and reduced the release of cytochrome c. Conclusion: Tilianin reduced apoptosis after I/R-induced AKI by the ERK/EGR1/BCL2L1 pathway. Our findings provided novel insights for the first time into the protective effect and underlying molecular mechanisms of tilianin on I/R-induced AKI.

Development of a multifunctional gold nanoplatform for combined chemo-photothermal therapy against oral cancer.

Aim: To design and fabricate a multifunctional drug-delivery nanoplatform for oral cancer therapy. Materials & methods: Polyethylene glycol-stabilized, PDPN antibody (PDPN Ab)- and doxorubicin (DOX)-conjugated gold nanoparticles (AuNPs) were prepared and evaluated for their cytotoxicity and antitumor efficacy in both chemotherapy and photothermal therapy. Results: The obtained (PDPN Ab)-AuNP-DOX system presents low toxicity, a high drug loading capacity and cellular uptake efficiency. Both in vitro and in vivo experiments demonstrate that (PDPN Ab)-AuNP-DOX has enhanced antitumor efficacy. Treatment with (PDPN Ab)-AuNP-DOX combined with laser irradiation exhibits superior antitumor effects. Conclusion: This (PDPN Ab)-AuNP-DOX system may be used as a versatile drug-delivery nanoplatform for targeted and combined chemo-photothermal therapy against oral cancer.

Tumor necrosis factor receptor-associated factor 6 contributes to malignant behavior of human cancers through promoting AKT ubiquitination and phosphorylation.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been found to be involved in carcinogenesis in multiple cancers. However, the precise role of TRAF6 in cancer has not been extensively investigated and remains largely unknown. In this study, we aimed to investigate the biological function of TRAF6 and its underlying molecular mechanisms in cancer. A positive correlation between poor tumor differentiation and TRAF6 expression status was observed in both oral cancer and breast cancer. Overexpression of TRAF6 promoted proliferation, migration, and G0 /G1 to S phase transition in tumor cells. Tumor necrosis factor receptor-associated factor 6-mediated AKT ubiquitination and subsequent phosphorylation played an essential role in the control of tumor cell malignant behavior. In vivo treatment with TRAF6, but not the E3 ligase deficient TRAF6 mutant, facilitated tumor growth. Our findings indicate that TRAF6 contributes to malignant behavior of human cancers through promoting AKT ubiquitination and phosphorylation. Therefore, TRAF6 could serve as a therapeutic target in cancers.

Serum miR-626 and miR-5100 are Promising Prognosis Predictors for Oral Squamous Cell Carcinoma.

Although serum microRNAs (miRNAs) are currently being considered as promising noninvasive biomarkers for cancers, their role in the prognosis of oral squamous cell carcinoma (OSCC) has not been elucidated. Here we aimed to identify serum miRNA biomarkers that could be used as prognosis predictors of OSCC. Methods: A cohort of 260 serum miRNA samples was assessed in a three-step approach that included a screening stage, a training stage, and a testing stage. The correlation between prognosis of OSCC and the miRNAs expression was comprehensively analyzed. Results: A two-miRNA signature involving miR-626 and miR-5100 has been developed. Patients defined to be high-risk group by the two-miRNA signature had significantly shortened median survival time compared with the low-risk group. In multivariate analysis, this two-miRNA signature was independently predictive of survival, and achieved a superior predictive value compared with that of traditional clinicopathologic factors such as pathology grade as well as tumor and node metastasis (TNM) stage. An integrated prognostic model combining the TNM stage and miRNA signature displayed the highest prognostic performance (AUC value: 0.787, specificity: 0.884, sensitivity: 0.573) compared to the TNM stage-alone (AUC value: 0.630, specificity: 0.526, sensitivity: 0.733) or miRNA signature-alone model (AUC value: 0.771, specificity: 0.768, sensitivity: 0.773). In addition, we found that OSCC tumor cells not only expressed a high level of these two miRNAs, but also secreted certain miRNAs into the extracellular environment, suggesting these miRNAs may originate from tumor cells. Conclusion: In our study, we established a two-miRNA signature that was strongly and independently associated with prognosis in OSCC, and may serve as a promising prognosis predictor.

Proteolytic Release of the p75NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis.

Resistance to anoikis allows cancer cells to survive during systemic circulation; however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75NTR) and subsequent generation of the p75NTR intracellular domain (ICD) endow cancer cells with resistance to anoikis. p75NTR ICD promoted expression of TNF receptor-associated factor 6 (TRAF6), a critical intermediary in p75NTR ICD-mediated signal transduction, at the translational level. Cell detachment-induced activation of EGFR triggered autoubiquitination of TRAF6 by facilitating its dimerization, subsequently activated NFκB, and eventually led to anoikis resistance. ADAM10 and p75NTR ICD also promoted tumor metastasis formation in vivo Together, our findings uncover a previously unknown function for the ADAM10-p75NTR ICD-TRAF6-NFκB axis in preventing anoikis and suggest ADAM10 and p75NTR ICD as potential cancer therapeutic targets.Significance: These findings identify the ADAM10-p75NTR ICD-TRAF6-NFκB signaling axis as a potential candidate for cancer therapy. Cancer Res; 78(9); 2262-76. ©2018 AACR.

Citrate attenuates vascular calcification in chronic renal failure rats.

Vascular calcification (VC) is a major contributor of cardiovascular dysfunction in chronic renal failure (CRF). Citrate binds calcium and inhibits the growth of calcium crystals. This present study intends to evaluate the effect of citrate on VC in adenine-induced CRF rats. The rats were randomly divided into five groups: the control group, the citrate control group, model group, model rats with low-dose treatment of citrate (216 mg/kg) and model rats with high-dose treatment of citrate (746 mg/kg). The rats were euthanized at 5 weeks with their blood and aorta in detection. The results showed that serum level of blood urea nitrogen, serum creatinine, phosphorus, calcium, and related renal failure function marker were elevated in the model group. Furthermore, the aortic calcium accumulation and alkaline phosphatase activity were significantly increased in the model group compared with control groups. Additionally, hematoxylin-eosin staining results demonstrated that the vascular calcification in aorta is significantly increased in the model group. Finally, the expression of VC-related proteins including bone morphogenetic protein and osteocalcin were increased in the model group, whereas alpha-smooth muscle actin was decreased in the model group compared with the control group. However, treatment with citrate caused a reversal effect of all the above events in a dose-dependent manner. In conclusion, citrate may attenuate vascular calcification in adenine-induced CRF rats.

[Study on the extracting of ursolic acid by uniform design].

Uniform design method was adopted to research the extraction of ursolic acid. The ethanol concentration, the extraction time, the liquid to solid ratio and the extraction times were researched by U7 (7(4)). The optimal conditions were achieved by optimization treatment and confirmed by experiment:the ethanol concentration being 75%, liquid to solid ratio being 7, extraction time 60 minutes, extracted two times.