ANGPTL3 is a novel HDL component that regulates HDL function.

BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) is secreted by hepatocytes and inhibits lipoprotein lipase and endothelial lipase activity. Previous studies reported the correlation between plasma ANGPTL3 levels and high-density lipoprotein (HDL). Recently ANGPTL3 was found to preferentially bind to HDL in healthy human circulation. Here, we examined whether ANGPTL3, as a component of HDL, modulates HDL function and affects HDL other components in human and mice with non-diabetes or type 2 diabetes mellitus. METHODS: HDL was isolated from the plasma of female non-diabetic subjects and type-2 diabetic mellitus (T2DM) patients. Immunoprecipitation, western blot, and ELISA assays were used to examine ANGPTL3 levels in HDL. Db/m and db/db mice, AAV virus mediated ANGPTL3 overexpression and knockdown models and ANGPTL3 knockout mice were used. The cholesterol efflux capacity induced by HDL was analyzed in macrophages preloaded with fluorescent cholesterol. The anti-inflammation capacity of HDL was assessed using flow cytometry to measure VCAM-1 and ICAM-1 expression levels in TNF-α-stimulated endothelial cells pretreated with HDL. RESULTS: ANGPTL3 was found to bind to HDL and be a component of HDL in both non-diabetic subjects and T2DM patients. Flag-ANGPTL3 was found in the HDL of transgenic mice overexpressing Flag-ANGPTL3. ANGPLT3 of HDL was positively associated with cholesterol efflux in female non-diabetic controls (r = 0.4102, p = 0.0117) but not in female T2DM patients (r = - 0.1725, p = 0.3224). Lower ANGPTL3 levels of HDL were found in diabetic (db/db) mice compared to control (db/m) mice and were associated with reduced cholesterol efflux and inhibition of VCAM-1 and ICAM-1 expression in endothelial cells (p < 0.05 for all). Following AAV-mediated ANGPTL3 cDNA transfer in db/db mice, ANGPTL3 levels were found to be increased in HDL, and corresponded to increased cholesterol efflux and decreased ICAM-1 expression. In contrast, knockdown of ANGPTL3 levels in HDL by AAV-mediated shRNA transfer led to a reduction in HDL function (p < 0.05 for both). Plasma total cholesterol, total triglycerides, HDL-c, protein components of HDL and the cholesterol efflux function of HDL were lower in ANGPTL3-/- mice than ANGPTL3+/+ mice, suggesting that ANGPTL3 in HDL may regulate HDL function by disrupting the balance of protein components in HDL. CONCLUSION: ANGPTL3 was identified as a component of HDL in humans and mice. ANGPTL3 of HDL regulated cholesterol efflux and the anti-inflammatory functions of HDL in T2DM mice. Both the protein components of HDL and cholesterol efflux capacity of HDL were decreased in ANGPTL3-/- mice. Our findings suggest that ANGPTL3 in HDL may regulate HDL function by disrupting the balance of protein components in HDL. Our study contributes to a more comprehensive understanding of the role of ANGPTL3 in lipid metabolism.

Central role of cardiac fibroblasts in myocardial fibrosis of diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM), a main cardiovascular complication of diabetes, can eventually develop into heart failure and affect the prognosis of patients. Myocardial fibrosis is the main factor causing ventricular wall stiffness and heart failure in DCM. Early control of myocardial fibrosis in DCM is of great significance to prevent or postpone the progression of DCM to heart failure. A growing body of evidence suggests that cardiomyocytes, immunocytes, and endothelial cells involve fibrogenic actions, however, cardiac fibroblasts, the main participants in collagen production, are situated in the most central position in cardiac fibrosis. In this review, we systematically elaborate the source and physiological role of myocardial fibroblasts in the context of DCM, and we also discuss the potential action and mechanism of cardiac fibroblasts in promoting fibrosis, so as to provide guidance for formulating strategies for prevention and treatment of cardiac fibrosis in DCM.

Role of advanced glycation end products on vascular smooth muscle cells under diabetic atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease and leading cause of cardiovascular diseases. The progression of AS is a multi-step process leading to high morbidity and mortality. Hyperglycemia, dyslipidemia, advanced glycation end products (AGEs), inflammation and insulin resistance which strictly involved in diabetes are closely related to the pathogenesis of AS. A growing number of studies have linked AGEs to AS. As one of the risk factors of cardiac metabolic diseases, dysfunction of VSMCs plays an important role in AS pathogenesis. AGEs are increased in diabetes, participate in the occurrence and progression of AS through multiple molecular mechanisms of vascular cell injury. As the main functional cells of vascular, vascular smooth muscle cells (VSMCs) play different roles in each stage of atherosclerotic lesions. The interaction between AGEs and receptor for AGEs (RAGE) accelerates AS by affecting the proliferation and migration of VSMCs. In addition, increasing researches have reported that AGEs promote osteogenic transformation and macrophage-like transformation of VSMCs, and affect the progression of AS through other aspects such as autophagy and cell cycle. In this review, we summarize the effect of AGEs on VSMCs in atherosclerotic plaque development and progression. We also discuss the AGEs that link AS and diabetes mellitus, including oxidative stress, inflammation, RAGE ligands, small noncoding RNAs.

Combined effects of voluntary running and liraglutide on glucose homeostasis, fatty acid composition of brown adipose tissue phospholipids, and white adipose tissue browning in db/db mice.

There is a potential therapeutic application targeting brown adipose tissue (BAT). Either voluntary running or liraglutide increases the thermogenesis of BAT in type 2 diabetes mellitus, but their combined effect is not yet clarified. Male leptin receptor-deficient db/db diabetic mice (n = 24) were randomly divided into voluntary running, liraglutide, voluntary running + liraglutide, and control groups (n = 6/group). Normal male C57 mice were the negative control (n = 6). Fasting blood glucose was monitored every week, plasma insulin and lipid profiles were analyzed, and thermogenic protein expression in BAT and white adipose tissue (WAT) were analyzed by the western blot. A total of 128 metabolites associated with phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, and ceramides were targeted in BAT. Compared to the control group, voluntary running or liraglutide treatment significantly lowered the blood glucose and increased the insulin level; the combined group showed a better effect than liraglutide alone. Hence, the combined treatment showed an enhanced hypoglycemic effect. Uncoupling protein 1 (UCP1) and OXPHOS protein expression in BAT and UCP1 in WAT were significantly increased after exercise training and liraglutide treatment. However, BAT metabolomics showed that compared to the control mice, nine fatty acids increased in the exercise group, six increased in the liraglutide group, and only three increased in the combined group. These results may suggest a higher hypoglycemic effect and the activation of BAT and WAT browning in the combined group.

ATP Secretion and Metabolism in Regulating Pancreatic Beta Cell Functions and Hepatic Glycolipid Metabolism.

Diabetes (DM), especially type 2 diabetes (T2DM) has become one of the major diseases severely threatening public health worldwide. Islet beta cell dysfunctions and peripheral insulin resistance including liver and muscle metabolic disorder play decisive roles in the pathogenesis of T2DM. Particularly, increased hepatic gluconeogenesis due to insulin deficiency or resistance is the central event in the development of fasting hyperglycemia. To maintain or restore the functions of islet beta cells and suppress hepatic gluconeogenesis is crucial for delaying or even stopping the progression of T2DM and diabetic complications. As the key energy outcome of mitochondrial oxidative phosphorylation, adenosine triphosphate (ATP) plays vital roles in the process of almost all the biological activities including metabolic regulation. Cellular adenosine triphosphate participates intracellular energy transfer in all forms of life. Recently, it had also been revealed that ATP can be released by islet beta cells and hepatocytes, and the released ATP and its degraded products including ADP, AMP and adenosine act as important signaling molecules to regulate islet beta cell functions and hepatic glycolipid metabolism via the activation of P2 receptors (ATP receptors). In this review, the latest findings regarding the roles and mechanisms of intracellular and extracellular ATP in regulating islet functions and hepatic glycolipid metabolism would be briefly summarized and discussed.

Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment.

In recent years, important changes have occurred in the field of diabetes treatment. The focus of the treatment of diabetic patients has shifted from the control of blood glucose itself to the overall management of risk factors, while adjusting blood glucose goals according to individualization. In addition, regulators need to approve new antidiabetic drugs which have been tested for cardiovascular safety. Thus, the newest class of drugs has been shown to reduce major adverse cardiovascular events, including sodium-glucose transporter 2 (SGLT2) and some glucagon like peptide 1 receptor (GLP1) analog. As such, they have a prominent place in the hyperglycemia treatment algorithms. In recent years, the role of DPP4 inhibitors (DPP4i) has been modified. DPP4i have a favorable safety profile and anti-inflammatory profile, do not cause hypoglycemia or weight gain, and do not require dose escalation. In addition, it can also be applied to some types of chronic kidney disease patients and elderly patients with diabetes. Overall, DPP4i, as a class of safe oral hypoglycemic agents, have a role in the management of diabetic patients, and there is extensive experience in their use.

Epigallocatechin-3-gallate ameliorates hepatic damages by relieve FGF21 resistance and promotion of FGF21-AMPK pathway in mice fed a high fat diet.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is considered to be one of the most common chronic liver diseases across worldwide. Epigallocatechin-3-gallate (EGCG) derived from extract of green tea and is well known for beneficial effects on anti-oxidative, anti-inflammatory, and anti-tumor activity. The present study aimed to implore its underlying mechanism for protective effect of NAFLD. METHODS: Mice were fed either high fat diet (HFD) or chow diet with or without EGCG treatment in HFD group, for up to 16 weeks. Histopathology, expression of lipid and glucose metabolism and lipogenesis-related gene expression were assessed. Primary mouse hepatocytes were treated with free fatty acids combined with different doses of EGCG for 48 h, expression of lipid and lipogenesis-related gene expression were assessed. RESULTS: The results showed that EGCG attenuated HFD- and FFA-induced lipid accumulation in vivo and in vitro. EGCG can decrease the oxidative stress and promote Nrf2 level. Meanwhile EGCG alleviated FGF21 resistance and elevated FGFR/AMPK expression, which suggested an unrecognized mechanism of EGCG in ameliorating NAFLD. CONCLUSIONS: EGCG attenuated hepatocytes damage and dysfunction in NAFLD by alleviating FGF21 resistance and improve FGFR/AMPK pathway, mitigating oxidative stress. Our studies verified that EGCG may become a promising drug to treat or relieve NAFLD.

Lipidomic profiling reveals distinct differences in plasma lipid composition in overweight or obese adolescent students.

INTRODUCTION: The relationship between dyslipidemia and obesity has been widely reported, but the global lipid profiles associated with the development of obesity still need to be clarified. An investigation into the association between the lipidomic plasma profile and adolescent obesity may provide new insights into the development of obesity. METHODS: Mass spectrometry coupled with liquid chromatography was applied to detect the global lipidome in the fasting plasma from 90 Chinese adolescents, including 34 obese adolescents, 26 overweight adolescents, and 30 adolescents with a normal body mass index (BMI). All participants underwent anthropometric measurements by using InBody. Clinical biochemical indicators were measured by Cobas Elecsys. RESULTS: Both qualitative and quantitative analyses revealed a gradual change in plasma lipid features among obese students, exhibiting characteristics close to overweight students, but differing significantly from normal students. Compared with normal and overweight students, levels of triglyceride (TG), 18-hydroxycortisol, isohumulinone A, and 11-dihydro-12-norneoquassin were up-regulated in the obese group, while phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysoPC (LPC), lysoPE (LPE), and phosphatidylinositol (PI) were significantly down-regulated in the obese group. Then, we conducted Venn diagrams and selected 8 significant metabolites from the 3 paired comparisons. Most of the selected features were significantly correlated with the anthropometric measurements. CONCLUSIONS: This study demonstrated evidence for a relationship between the eight significant metabolites with obese adolescents. These lipid features may provide a basis for evaluating risk and monitoring the development of obesity.

Dipeptidyl peptidase-4 (DPP4) inhibitor sitagliptin alleviates liver inflammation of diabetic mice by acting as a ROS scavenger and inhibiting the NFκB pathway.

As a common chronic metabolic disease, the development of diabetes mellitus (DM) may also be accompanied by liver damage and inflammatory disorders. Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP4, also known as CD26), which is clinically used for DM treatment. However, the mechanism of sitagliptin's efficiency in liver diseases is largely unknown. In this study, mice suffering from streptozotocin (STZ) exhibit elevated liver DPP4 expression and activity, as well as inflammatory and chronic liver injury phenotype, whereas specifically inhibiting the activity of DPP4 in mouse liver tissues and hepatocytes by sitagliptin contributes to decreased cytokines, oxidative stress, cell apoptosis, and inflammation in STZ-induced diabetic mice. Moreover, sitagliptin reduced TNFα or LPS-induced cellular reactive oxygen species (ROS) level, cell apoptosis, and protein expression in the NFκB signaling pathway in HepG2 cells or primary mouse hepatocytes. Altogether, our study confirms that sitagliptin may protect liver tissue by alleviating ROS production and NFκB signaling activation, providing a putative mechanism for preventing the development of diabetic liver disease.

Associations between exposure to polycyclic aromatic hydrocarbons and metabolic syndrome in U.S. adolescents: Cross-sectional results from the National Health and Nutrition Examination Survey (2003-2016) data.

BACKGROUND: The metabolic syndrome is a constellation of risk factors, including abdominal obesity, hypertension, dyslipidemia, and hyperglycemia. Polycyclic aromatic hydrocarbons (PAHs) constitute a group of chemicals that are formed during the incomplete combustion of coal, oil and gas, garbage, and other organic substances. In the occupational exposure population, PAHs exposure increased the prevalence ratio of metabolic syndrome. However, the effect of PAHs on prevalence of metabolic syndrome in adolescents has not been reported. Because of the propensity for childhood metabolic risk to track into adulthood, there is a great need to identify risk factors for childhood metabolic syndrome. METHOD: Using data from the 2003-2016 National Health and Nutrition Examination Survey. We defined metabolic syndrome using a modified version of the National Cholesterol Education Program Adult Treatment Panel Ⅲ definition for adolescents. Weighted logistic regression was used to calculate the odds ratio and 95 % confidence intervals for each biomarker. In addition, we applied the weighted quantile sum (WQS) regressions to adolescent metabolic syndrome to reveal the multiple exposure effects and relative weights of each PAH. RESULTS: Among the 827 adolescents, 183 (22.13 %) had metabolic syndrome. The levels of 2-hydroxynaphthalene (2-NAP), 2-hydroxyphenanthrene (2-PHE), 2-hydroxyfluorene (2-FLU), 1-hydroxynaphthalene (1-NAP), 3-hydroxyfluorene (3-FLU) and 1-hydroxypyrene (1-PYR) were higher in the group of adolescents with metabolic syndrome. There were positive associations between higher concentrations of 2-NAP, 2-FLU and odds of metabolic syndrome after adjustment, which odds ratios (ORs) in the 3rd tertile were 2.22 (95%CI:1.45-3.44) and 2.09 (95%CI:1.36-3.10), respectively. In subgroups analysis, the ORs between the 3 tertile concentrations of 2-NAP, 2-PHE and high fasting blood glucose (FBG) were 2.20 (95%CI:1.37-3.57) and 1.99 (95%CI:1.16-3.48). CONCLUSION: The present study suggested that PAHs may be associated with odds of metabolic syndrome as well as individual metabolic syndrome components among adolescents. A cohort study should be designed to clarify the cause and effect between PAHs and metabolic syndrome in future research.

PM2.5 promotes ß cell damage by increasing inflammatory factors in mice with streptozotocin.

Emerging evidence indicates that exposure to fine particulate matter contributes to the onset of diabetes. The present study aimed to investigate the mechanism of particulate matters (PM)2.5 affecting glucose homeostasis in mice with type 1 diabetes mellitus. Male C57BL/6 mice were housed under filtered air (FA) or PM2.5 for 12 weeks and then received intraperitoneal injection of streptozotocin (STZ; 40 mg/kg) or acetic buffer daily for 5 days. At 4 weeks after the last injection, fasting glucose was tested. In the plasma and liver, cholesterol levels were determined by cholesterol oxidase-peroxidase and triglyceride levels were determined by triglycerophosphate oxidase-peroxidase. Homeostasis model assessment of ß cell function (Homa-ß) was computed based on fasting insulin and glucose levels. Interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNFα) levels in plasma, visceral adipose tissues, RAW264.7 macrophages and MIN6 pancreatic ß cells treated with PM2.5 (0-50 µg/ml) were quantified via ELISA. Before STZ injection, fasting blood glucose (FBG) levels were similar between FA and PM2.5 groups. After STZ injection, FBG levels were higher in mice pre-exposed to PM2.5 compared with those pre-exposed to FA. When taking FBG levels ≥7 mmol/l as the criteria for impaired glucose level, its incidence was 53.3% and 77.8% in FA and PM2.5 groups, respectively. Independent of STZ injection, IL-1ß levels in the adipose tissue were upregulated in mice pre-exposed to PM2.5 compared with FA. The addition of PM2.5 stimulated IL-1ß and TNFα production in macrophages and pancreatic ß cells, and inhibited the secretion of insulin from MIN6 cells in a dose-dependent manner. In conclusion, pre-exposure of PM2.5 impaired pancreatic ß cells in mice upon STZ injection, partially via enhanced inflammation, and suppressed the secretion of insulin.

Higher levels of circulating ANGPTL2 are associated with macular edema in patients with type 2 diabetes.

ABSTRACT: Macular edema (ME) is an inflammatory disease characterized by increased microvascular permeability. Here, we proposed that plasma angiopoietin-like protein 2 (ANGPTL2) level may be related to the severity of ME patients with type 2 diabetes mellitus (T2DM). In this cross-sectional study, 172 T2DM patients were recruited and divided into clinically significant macular edema (CSME), non-CSME (nCSME), and control groups. Serum ANGPTL2 level was quantified by ELISA and best corrected vision acuity (BCVA) was detected. After adjust age, sex, body mass index (BMI), and duration of diabetes variables, ANGPTL2 performed statistics difference among CSME-, nCSME-groups, and control group (4.46 [3.97, 4.96, 95%CI] ng/mL in CSME group, 3.80 [3.42, 4.18, 95%CI] ng/mL in nCSME-group, 3.33 [3.03, 3.63, 95%CI] ng/mL in control, P < .01). After adjustment of confounding factors, high levels of circulating ANGPTL2 were related with the diagnosis of ME, BCVA, and C reactive protein (CRP) through univariate regression analysis (P < .05). Meanwhile, in the multiple regression model, ANGPTL2 took the mainly effect proportion for the diagnosis of diabetic macular edema (DME), with a LogWorth value 3.559 (P < .001). Our study suggested that elevated circulating ANGPTL2 may be associated with the development of DME and the severity of visual impairment in patients with type 2 diabetes.

Circulating Angptl3 and Angptl8 Are Increased in Patients with Hypothyroidism.

PURPOSE: Angiopoietin-like proteins (Angptls) play critical roles in biological processes, primarily in lipid metabolism. The functional state of the thyroid has a profound influence on metabolism in the human body. Therefore, the aim of this study was to investigate possible changes in serum Angptl3, 4, and 8 levels in hypothyroid patients. METHODS: The study included 29 patients with clinical hypothyroidism, 30 patients with subclinical hypothyroidism, and 29 healthy subjects. Baseline clinical indices, including serum thyroid function tests, were recorded and serum Angptl3, 4, and 8 levels were measured across the three groups. RESULTS: Serum Angptl3 and 8 levels were significantly higher in the hypothyroid groups compared to the control group (p < 0.05). There were no differences in Angptl4 levels among the three groups (p > 0.05). Positive correlations were identified between Angptl3 and high-density lipoprotein cholesterol (r = 0.431, p < 0.001), and there was a negative correlation between Angptl3 and total tri-iodothyronine (TT3) (r = -0.220, p = 0.047) and free tri-iodothyronine (r = - 0.279, p = 0.013) levels. Angptl8 was positively correlated with triglyceride (r = 0.267, p = 0.012) and cholesterol levels (r= 0.235, p = 0.028) but was negatively correlated with tri-iodothyronine (r = -0.24, p = 0.031). Furthermore, we used receiver operating characteristic curve analysis to evaluate the diagnostic performance of Angptl3 and 8 in discriminating thyroid dysfunction. The area under curve for detecting thyroid dysfunction based on Angptl3 and Angptl8 was 0.763. CONCLUSIONS: Our data show that serum Angptl3 and 8 levels are increased in clinical and subclinical hypothyroid patients and that Angptl3 and 8 may serve as possible biomarkers of hypothyroid disease.

Activation of brown adipocytes by placental growth factor.

Gestational diabetes mellitus (GDM) is a type of diabetes and occurs during pregnancy. Brown adipose tissue (BAT) improves glucose homeostasis and mitigates insulin resistance, however, its activity is reduced in GDM. Placenta growth factor (PlGF) is an angiogenic factor produced by placental trophoblasts. Nevertheless, whether and how PlGF could affect BAT function in GDM are not defined. To investigate this question, 91 non-diabetic pregnant participants and 73 GDM patients were recruited to Gynaecology and Obstetrics Centre in Lu He hospital. Serum levels of PlGF were quantified by ELISA. Skin temperature was measured by far infrared thermography in the supraclavicular region where classical BATs were located. The direct effect of PlGF on BAT function was explored using the established human preadipocyte differentiation system. Thereby, we demonstrated that serum levels of PlGF were lower in GDM patients compared with controls, which was accompanied by decreased skin temperature in the supraclavicular region. By qPCR and western blot, mRNA and protein expression of UCP1 and OXPHOS were elevated in differentiated adipocytes treated with PlGF. PlGF stimulated mitochondrion transcription and increased copy number of mitochondrial. When subjected for respirometry, PlGF-treated differentiated adipocytes showed higher oxygen consumption rates than controls. PlGF induced AMPK phosphorylation and blockade of AMPK phosphorylation blunted UCP1 and OXPHOS expression in differentiated adipocytes. PlGF administration reduced cholesterol and triglyceride content in the liver and improved insulin sensitivity in db mice compared with control. In Conclusion, PlGF could activate BAT function. Downregulation of PlGF might contribute to the reduced BAT activity in GDM.

miR-706 inhibits the oxidative stress-induced activation of PKCα/TAOK1 in liver fibrogenesis.

Oxidative stress induces the activation of liver fibrogenic cells (myofibroblasts), thus promoting the expression of fibrosis-related genes, leading to hepatic fibrogenesis. MicroRNAs (miRNAs) are a new class of small RNAs ~18-25 nucleotides in length involved in post-transcriptional regulation of gene expression. Wound-healing and remodeling processes in liver fibrosis have been associated with changes in hepatic miRNA expression. However, the role of miR-706 in liver fibrogenesis is currently unknown. In the present study, we show that miR-706 is abundantly expressed in hepatocytes. Moreover, oxidative stress leads to a significant downregulation of miR-706, and the further reintroduction of miR-706 inhibits oxidative stress-induced expression of fibrosis-related markers such as α-SMA. Subsequent studies revealed that miR-706 directly inhibits PKCα and TAOK1 expression via binding to the 3'-untranslated region, preventing epithelial mesenchymal transition. In vivo studies showed that intravenous injection of miR-706 agomir successfully increases hepatic miR-706 and decreases α-SMA, PKCα, and TAOK1 protein levels in livers of carbon tetrachloride (CCl4)-treated mice. In summary, this study reveals a protective role for miR-706 by blocking the oxidative stress-induced activation of PKCα/TAOK1. Our results further identify a major implication for miR-706 in preventing hepatic fibrogenesis and suggest that miR-706 may be a suitable molecular target for anti-fibrosis therapy.

Postconditioning attenuates renal ischemia-reperfusion injury by mobilization of stem cells.

BACKGROUND: We recently showed that reactive oxygen species (ROS) and mitochondrial DNA damage and deletions were attenuated by postconditioning (POC). It is not known, however, whether a population of progenitor cells is recruited by POC and is responsible for repair of renal tubular epithelial cells after ischemic injury. METHODS: The model of renal POC was induced by 45 min clamping of the left renal artery and right nephrectomy followed by 7 min of short-time full reperfusion and 3 cycles of 30 s ischemia and 30 s reperfusion. The lymphocyte compartment of peripheral blood was evaluated by fluorescence-activated cell sorting (FACS) to determine expression of the bone marrow-derived progenitor cell markers CXC-chemokine receptor 4 (CXCR4), c-Kit, and CD34, at 12 h, 1 day and 3 days post-ischemia. Serum and kidney tissue were collected for analysis at 3 and 7 days post-ischemia. RESULTS: Renal functional and structural recovery was markedly improved by POC, which increased the number of CXCR4(+) and CD34(+) stem cells in peripheral blood and kidney tissue. Inhibition of ROS burst by POC was likely associated with increased hypoxia-inducible factor-1 expression, which may further promote stromal cell-derived factor 1 (SDF-1) expression. CONCLUSIONS: The mechanisms of stem cell recruitment to the injured foci mobilized by POC appear to be mediated by moderate oxidative stress, which may lead to increased SDF-1 expression.