Deletion of endothelial IGFBP5 protects against ischaemic hindlimb injury by promoting angiogenesis.

BACKGROUND: Angiogenesis is critical for forming new blood vessels from antedating vascular vessels. The endothelium is essential for angiogenesis, vascular remodelling and minimisation of functional deficits following ischaemia. The insulin-like growth factor (IGF) family is crucial for angiogenesis. Insulin-like growth factor-binding protein 5 (IGFBP5), a binding protein of the IGF family, may have places in angiogenesis, but the mechanisms are not yet completely understood. We sought to probe whether IGFBP5 is involved in pathological angiogenesis and uncover the molecular mechanisms behind it. METHODS AND RESULTS: IGFBP5 expression was elevated in the vascular endothelium of gastrocnemius muscle from critical limb ischaemia patients and hindlimb ischaemic (HLI) mice and hypoxic human umbilical vein endothelial cells (HUVECs). In vivo, loss of endothelial IGFBP5 (IGFBP5EKO) facilitated the recovery of blood vessel function and limb necrosis in HLI mice. Moreover, skin damage healing and aortic ring sprouting were faster in IGFBP5EKO mice than in control mice. In vitro, the genetic inhibition of IGFBP5 in HUVECs significantly promoted tube formation, cell proliferation and migration by mediating the phosphorylation of IGF1R, Erk1/2 and Akt. Intriguingly, pharmacological treatment of HUVECs with recombinant human IGFBP5 ensued a contrasting effect on angiogenesis by inhibiting the IGF1 or IGF2 function. Genetic inhibition of IGFBP5 promoted cellular oxygen consumption and extracellular acidification rates via IGF1R-mediated glycolytic adenosine triphosphate (ATP) metabolism. Mechanistically, IGFBP5 exerted its role via E3 ubiquitin ligase Von Hippel-Lindau (VHL)-regulated HIF1α stability. Furthermore, the knockdown of the endothelial IGF1R partially abolished the reformative effect of IGFBP5EKO mice post-HLI. CONCLUSION: Our findings demonstrate that IGFBP5 ablation enhances angiogenesis by promoting ATP metabolism and stabilising HIF1α, implying IGFBP5 is a novel therapeutic target for treating abnormal angiogenesis-related conditions.

An analysis of the relationship between donor and recipient biomarkers and kidney graft function, dysfunction, and rejection.

BACKGROUND: The study aimed to find predictive biomarkers to evaluate donor kidney function to predict graft dysfunction as well as to assess an early signs of acute graft rejection. METHOD: Twenty-seven deceased donors and 54 recipients who underwent a successful kidney transplantation were enrolled in the study. An assessment was made in serum and urine from donors and recipients to measure the following biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase 2 (TIMP-2) and urinary N-acetyl-b-D-glucosaminidase (uNAG). These biomarkers were used to establish a model for predicting a reduced graft function (RGF) classified as either a delayed or slow graft function. RESULT: Our analysis suggest that out of four tested biomarkers, the serum TIMP-2 and uNAG levels of the donors had a predictive value for RGF; the area under the receiver operating characteristic curves (AUROC) of serum TIMP-2 and uNAG were 0.714 and 0.779, respectively. The combined best fitting prediction model of serum TIMP-2, uNAG, and creatinine levels was better in predicting RGF than the serum creatinine level alone. In addition, the recipient serum TIMP-2 level on the third day post-transplantation (D3) was associated with the estimated glomerular filtration rate (eGFR) on the seventh day post-transplantation (D7; OR 1.119, 95% CI 1.016-1.233, p = 0.022). Furthermore, the ROC curve value revealed that the AUROC of TIMP-2 on D3 was 0.99 (95% CI 0.97-1, p < 0.001), and this was the best predictive value of the renal function on D7. CONCLUSIONS: Donor serum TIMP-2 and uNAG levels are useful predictive biomarkers because they can provide the donor-based prediction for RGF.

Acacetin attenuates diabetes-induced cardiomyopathy by inhibiting oxidative stress and energy metabolism via PPAR-α/AMPK pathway.

Diabetic cardiomyopathy seriously affects the life quality of diabetic patients and can lead to heart failure and death in severe cases. Acacetin was reported to be an anti-oxidant and anti-inflammatory agent in several cardiovascular diseases. However, the effect of acacetin on diabetic cardiomyopathy was not understood. This study was designed to explore the therapeutic effect of acacetin on diabetic cardiomyopathy and the potential mechanism with in vitro and in vivo experimental techniques. In cultured neonatal rat cardiomyocytes and H9C2 cardiac cells, acacetin (0.3, 1, 3 µM) showed effective protection against high glucose-induced injury in a concentration-dependent manner. Acacetin countered high glucose-induced increase of Bax and decrease of Bcl-2, SOD1, and SOD2. In streptozotocin-induced rat diabetic cardiomyopathy model, treatment with acacetin prodrug (10 mg/kg, s.c., b.i.d.) significantly improved the cardiac function and reduced myocardial injury, and reversed the increase of serum MDA, Ang Ⅱ, and IL-6 levels and myocardial Bax and IL-6, and the decrease of serum SOD, indicating that acacetin plays a cardioprotective effect by inhibiting oxidative stress, inflammation, and apoptosis. In addition, both in vitro and in vivo experimental results showed that acacetin increased the expression of PPAR-α and pAMPK, indicating that PPAR-α and pAMPK are potential targets of acacetin for the protection against diabetic cardiomyopathy. This study demonstrates the new application of acacetin for treating diabetic cardiomyopathy.

miR-1293 Suppresses Tumor Malignancy by Targeting Hydrocyanic Oxidase 2: Therapeutic Potential of a miR-1293/Hydrocyanic Oxidase 2 Axis in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is a common cancer, and extensive research suggests that microRNA may play an important role in the progression of RCC. The emphasis of this article was to reveal the function and mechanism of microRNA-1293(miR-1293) in the development of RCC tumors. First, the authors carried out bioinformatics analysis. The differential expression of miR-1293 in RCC tumor and normal cells was analyzed using the data from The Cancer Genome Atlas database, and Kaplan-Meier survival analysis was carried out to test the survival rate. Subsequently, the miR-1293 expression in RCC cell lines was examined by quantitative real-time PCR. Then Cell counting kit-8 and Transwell assays were executed to detect the function of miR-1293 in RCC. Bioinformatics prediction, western blotting, and dual-luciferase reporter assay were set to check the target gene of miR-1293. Finally, they conducted rescue experiments to verify whether the regulation of miR-1293 on the biological function of RCC cells was achieved by regulating hydrocyanic oxidase 2 (HAO2). Bioinformatics results showed that miR-1293 was highly expressed in RCC, and the miR-1293 high-expression group showed a lower survival rate than the miR-1293 low-expression group, which suggested that the high expression of miR-1293 was related to unfavorable prognosis in RCC. Subsequent assays evidenced that upregulation of miR-1293 expression significantly increased the cell viability and promoted cell migration and invasion in RCC. Silencing miR-1293 expression showed opposite results. Furthermore, HAO2 was confirmed to be a direct target gene of miR-1293 by dual-luciferase reporter assay, and miR-1293 negatively regulated the expression of HAO2. Moreover, rescue experiments evidenced that miR-1293 reduced the cell viability, invasion, and migration of RCC by regulating HAO2. In sum, miR-1293 can regulate the viability, invasion, and migration of RCC tumor cells by targeting HAO2, suggesting that miR-1293 can be used as a new biomarker for clinical treatment of RCC.