Publications by authors named "Chang Chu"

35 Publications

Osteoprotegerin is an independent risk factor predicting death in stable renal transplant recipients.

Clin Nephrol 2021 May 27. Epub 2021 May 27.

Background: Vascular calcification is common in chronic kidney disease and is associated with significant cardiovascular morbidity and mortality. One of the important factors regulating vascular calcification is osteoprotegerin (OPG). There are, however, limited data on the impact of OPG on all-cause mortality and graft loss in kidney transplant recipients so far. Given its impact on vascular calcification, the aim of our study is to analyze whether OPG was a risk factor of all-cause mortality and graft loss in 600 stable kidney transplant recipients.

Materials And Methods: 600 stable renal transplant recipients (367 women, 233 men) were followed for all-cause mortality and graft loss for 3 years. Blood and urine samples for analysis and clinical data were collected at study entry. We performed Kaplan-Meier survival analysis and Cox regression models considering confounding factors such as age, estimated glomerular filtration rate (eGFR), cold ischemia time, HbA1c, phosphorus, calcium, and albumin.

Results: 65 patients died, and 38 patients had graft loss during the observation period. The OPG baseline concentrations had no effect on graft loss, whereas Kaplan-Meier survival curve showed that baseline plasma OPG concentrations were associated with all-cause mortality in stable kidney transplant recipients (p < 0.0001, log-rank test). After multiple Cox regression analysis adjusting for age, eGFR, cold ischemia time, HbA1c, phosphorus, calcium, and albumin, plasma levels of OPG remained an independent predictor of all-cause mortality (HR, 1.181; 95%CI 1.035 - 1.347; p = 0.014).

Conclusion: Baseline plasma OPG is an independent risk factor for all-cause mortality but not graft loss in patients after kidney transplantation.
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http://dx.doi.org/10.5414/CN110470DOI Listing
May 2021

Relationship Between Vitamin D and Hormones Important for Human Fertility in Reproductive-Aged Women.

Front Endocrinol (Lausanne) 2021 14;12:666687. Epub 2021 Apr 14.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.

Vitamin D deficiency is very common in women of reproductive age. Studies in animals suggests a link between vitamin D and reproductive hormone biosynthesis. A systematic analysis of the correlation of reproductive hormones in reproductive-aged women with both total and free vitamin D was, however, not done so far. This cross-sectional study was performed in 351 healthy reproductive age Caucasian women (median age, 28.0 years; interquartile ranges, 24.7-31.0 years). We measured serum levels of both total and free 25(OH)D, endocrinological, hematological and biochemical parameters. Spearman's rank correlations were performed to assess the correlation between 25(OH)D metabolites and selected parameters. Total vitamin D and free vitamin D measurements correlated well (rho=0.912, p < 0.0001). Both total 25(OH)D and free 25(OH)D showed significant negative correlation with FAI (rho=-0.229, p<0.0001 and rho=-0.195, p<0.0001 for total and free 25(OH)D, respectively); LH (rho=-0.177, p=0.001 and rho=-0.114, p=0.04 for total and free 25(OH)D, respectively), testosterone (rho=-0.174, p=0.001 and rho=-0.190, p<0.0001 for total and free 25(OH)D, respectively) and AMH (rho=-0.130, p=0.015 and rho=-0.107, p=0.047 for total and free 25(OH)D, respectively). Our study showed comparable correlations of both total and free 25(OH)D with endocrinological parameters, i.e. inverse correlations with free androgen index, luteinizing hormone, testosterone, LH/FSH ratio, androstenedione and anti-Müllerian hormone, and also with hematological and biochemical parameters, i.e. inverse correlations with erythrocytes, hsCRP and leukocytes count, and positive correlation with transferrin saturation, mean corpuscular hemoglobin and mean corpuscular volume in healthy reproductive age women.
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http://dx.doi.org/10.3389/fendo.2021.666687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081388PMC
April 2021

C-terminal and intact FGF23 in kidney transplant recipients and their associations with overall graft survival.

BMC Nephrol 2021 Apr 8;22(1):125. Epub 2021 Apr 8.

Fifth Department of Medicine (Nephrology/ Endocrinology/ Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.

Background: Increased fibroblast growth factor 23 (FGF23) is a risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease. Limited data exist comparing the association of either c-terminal FGF23 (cFGF23) or intact FGF23 (iFGF23) in kidney transplant recipients (KTRs) with overall (all-cause) graft loss.

Methods: We conducted a prospective observational cohort study in 562 stable kidney transplant recipients. Patients were followed for graft loss and all-cause mortality for a median follow-up of 48 months.

Results: During a median follow-up of 48 months, 94 patients had overall graft loss (primary graft loss or death with functioning graft). Both cFGF23 and iFGF23 concentrations were significantly higher in patients with overall graft loss than those without (24.59 [11.43-87.82] versus 10.67 [5.99-22.73] pg/ml; p < 0.0001 and 45.24 [18.63-159.00] versus 29.04 [15.23-60.65] pg/ml; p = 0.002 for cFGF23 and iFGF23, respectively). Time-dependent ROC analysis showed that cFGF23 concentrations had a better discriminatory ability than iFGF23 concentrations in predicting overall (all-cause) graft loss. Cox regression analyses adjusted for risk factors showed that cFGF23 (HR for one unit increase of log transformed cFGF23: 1.35; 95% CI, 1.01-1.79; p = 0.043) but not iFGF23 (HR for one unit increase of log transformed iFGF23: 0.97; 95% CI, 0.75-1.25; p = 0.794) was associated with the overall graft loss.

Conclusion: Elevated cFGF23 concentrations at baseline are independently associated with an increased risk of overall graft loss. iFGF23 measurements were not independently associated with overall graft loss. The cFGF23 ELISA might detect bioactive FGF23 fragments that are not detected by the iFGF23 ELISA.
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http://dx.doi.org/10.1186/s12882-021-02329-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033679PMC
April 2021

Sex Dependent Association of Vitamin D with Insulin Resistance.

J Clin Endocrinol Metab 2021 Apr 1. Epub 2021 Apr 1.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany.

Background: Animal studies suggested that vitamin D might decrease insulin resistance. Estrogen increased insulin sensitivity and glucose tolerance in rodents. However, sex-specific association of vitamin D with insulin resistance in humans remains unclear.

Objectives: To investigate the sex-dependency of the association of insulin resistance and 25(OH)D in a large Caucasian population.

Methods: Cross-sectional study from out-patients' blood samples with measurements of 25(OH)D and HOMA-IR drawn at exactly the same day (N=1887). This cohort was divided into three groups: i) group with vitamin D deficiency (n=1190), ii) group with vitamin D sufficiency (N=686)), iii) vitamin D excess groups (n=11), the vitamin D excess group was excluded from further analysis due to the small size.

Results: Analysis of the entire study population showed that serum 25-hydroxyvitamin D was inversely associated with HOMA-IR (rs=-0.19, P<0.0001). When considering the vitamin D status, this association was only seen in the vitamin D deficiency group, but not in the vitamin D sufficient group. The correlation was sex-dependent: HOMA-IR was inversely correlated with vitamin D in women with vitamin D deficiency (rs=-0.26, P<0.0001) but not in men with vitamin D deficiency (rs=0.01, P=0.714). After multivariate linear regression analysis considering confounding factors, this relationship was again only seen in women.

Conclusion: Vitamin D was inversely and independently associated with insulin resistance only in women with vitamin D deficiency. Based on our data, we suggest that in particular vitamin D deficient women might benefit from vitamin D substitution by improving insulin resistance. This, however, needs to be proven in adequately designed double-blind placebo-controlled clinical studies.
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http://dx.doi.org/10.1210/clinem/dgab213DOI Listing
April 2021

Reference values for free 25-hydroxy-vitamin D based on established total 25-hydroxy-vitamin D reference values.

J Steroid Biochem Mol Biol 2021 Jun 16;210:105877. Epub 2021 Mar 16.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Institute of Medical Diagnostics, IMD Berlin-Potsdam, Berlin, Germany; Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. Electronic address:

Measurements of total 25-hydroxyvitamin D (t25(OH)D) are currently primarily used to assess the vitamin D status. The lipophilic cell membrane can only be passed by the un-bound form of 25-hydroxyvitamin D: free 25-hydroxyvitamin D (f25(OH)D). It is thought that f25(OH)D does reflect its biological actions better than t25(OH)D. However, as of today, there are no established guidelines for the clinical use of f25(OH)D. We analysed 5060 patients with simultaneous measurements of free and total 25(OH). Linear regression was used to study the relationship between free 25(OH)D and total 25(OH)D. We reviewed and used the established t25(OH)D reference values and determined the slope of the relationship between them to calculate reference values for f25(OH)D. F25(OH)D and t25(OH)D showed a strong positive linear (r = 0.8395, p < 0.0001) correlation. The slope of the relationship was 0.2833 ± 0.00257. The recommended threshold level of f25(OH)D is 8.499 pg/mL, corresponding to a target concentration for t25(OH)D of at least 30 ng/mL considered as sufficient in most of the international vitamin D guidelines. The upper limit for vitamin D is less clear in the guidelines. Most experts favour an upper limit for t25(OH)D of 100 ng/mL. This is equivalent to 28.330 pg/mL f25OHD. We established based on international guidelines for t25(OH)D reference values for f25(OH)D that are urgently needed for clinical use of f25(OH)D. However, clinical studies with f25(OH)D to confirm our suggestions are needed but will take time.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105877DOI Listing
June 2021

Opposite correlation of 25-hydroxy-vitamin D- and 1,25-dihydroxy-vitamin D-metabolites with gestational age, bone- and lipid-biomarkers in pregnant women.

Sci Rep 2021 Jan 21;11(1):1923. Epub 2021 Jan 21.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.

25-Hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)D) need to be bound to carrier proteins to be transported to their target cells. The majority of either 25OHD or 1,25(OH)D is bound to vitamin D-binding protein (DBP), a smaller fraction is bound to albumin and only very small amounts of 25OHD or 1,25(OH)D are free. Albumin-bound 25OHD or 1,25(OH)D is relatively easily available after dissociation from albumin. Thus, the sum of free and albumin-bound forms is called bioavailable 25OHD and bioavailable 1,25(OH)D. Total 25OHD and 1,25(OH)D are defined as the sum of free, albumin-bound and DBP-bound 25OHD and 1,25(OH)D, respectively. This cross-sectional study in 427 pregnant women compared the correlation of the six vitamin D compounds with biomarkers of bone health, lipid metabolism, kidney function, endocrine parameters, and group B water-soluble vitamins. Among the 25OHD metabolites analysed, total 1,25(OH)D showed clearly the best correlation with calcium, bone-specific alkaline phosphatase, adiponectin, LDL, HDL, urea, thyroxine, and group B water-soluble vitamins. When comparing the three 25OHD metabolites, both free 25OHD and bioavailable 25OHD showed overall good correlations with calcium, bone-specific alkaline phosphatase, adiponectin, LDL, HDL, urea, thyroxine, triiodothyronine, and group B water-soluble vitamins, The correlations of 1,25(OH)D and 25OHD metabolites went always in opposite directions. Only PTH correlates always inversely with all six vitamin D compounds. In conclusion, free 25(OH)D and bioavailable 25(OH)D are more precise determinants of the vitamin D status than total 25(OH)D in normal pregnancy, whereas total 1,25(OH)D is superior to free and bioavailable 1,25(OH)D. Except for PTH, correlations of 25(OH)D and 1,25(OH)D metabolites with typical clinical chemistry readouts go in opposite directions.
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http://dx.doi.org/10.1038/s41598-021-81452-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820257PMC
January 2021

Comparison of infection risks and clinical outcomes in patients with and without SARS-CoV-2 lung infection under renin-angiotensin-aldosterone system blockade: Systematic review and meta-analysis.

Br J Clin Pharmacol 2021 06 18;87(6):2475-2492. Epub 2020 Dec 18.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany.

Aims: Angiotensin-converting enzyme-2 (ACE2) is the receptor for SARS-CoV-2. Animal studies suggest that renin-angiotensin-aldosterone system (RAAS) blockers might increase the expression of ACE2 and potentially increase the risk of SARS-CoV-2 infection.

Methods And Results: The effect of ACE inhibitor (ACEI) treatment on the pneumonia incidence in non-COVID-19 patients (25 studies, 330 780 patients) was associated with a 26% reduction of pneumonia risk (odds ratio [OR]: 0.74, P < .001). Pneumonia-related death cases in ACEI-treated non-COVID-19 patients were reduced by 27% (OR: 0.73, P = .004). However, angiotensin II receptor blockers (ARB) treatment (10 studies, 275 621 non-COVID-19 patients) did not alter pneumonia risk in patients. Pneumonia-related death cases in ARB-treated non-COVID-19 patients was analysed only in 1 study and was significantly reduced (OR, 0.47; 95% confidence interval, 0.30 to 0.72). Results from 11 studies (8.4 million patients) showed that the risk of getting infected with the SARS-CoV-2 virus was reduced by 13% (OR: 0.87, P = .014) in patients treated with ACEI, whereas analysis from 10 studies (8.4 million patients) treated with ARBs showed no effect (OR, 0.92, P = .354). Results from 34 studies in 67 644 COVID-19 patients showed that RAAS blockade reduces all-cause mortality by 24% (OR = 0.76, P = .04).

Conclusion: ACEIs reduce the risk of getting infected with the SARS-CoV-2 virus. Blocking the RAAS may decrease all-cause mortality in COVID-19 patients. ACEIs also reduce the risk of non-COVID pneumonia. All-cause mortality due to non-COVID pneumonia is reduced by ACEI and potentially by ARBs.
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http://dx.doi.org/10.1111/bcp.14660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753617PMC
June 2021

Rejuvenated Circulating Endothelial Progenitor Cells and Nitric Oxide in Premenopausal Women with Hyperhomocysteinemia.

Cardiol Res Pract 2020 31;2020:5010243. Epub 2020 Oct 31.

Department of Infectious Diseases, The 3rd Affiliated Hospital, Sun Yat-Sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou 510630, China.

Hyperhomocysteinemia (HHcy) induced endothelial dysfunction is associated with disturbance in circulating endothelial progenitor cells (EPCs). Nevertheless, whether this unfavorable effect of HHcy on circulating EPCs also exists in premenopausal women is still unknown. Therefore, this leaves an area for the investigation of the difference on the number and activity of circulating EPCs in premenopausal women with hyperhomocysteinemia and its underlying mechanism. The number of circulating EPCs was measured by fluorescence-activated cell sorter analysis, as well as DiI-acLDL and lectin fluorescent staining. The migration and proliferation of circulating were evaluated by the Transwell chamber assay and MTT. Additionally, the endothelial function and levels of nitric oxide (NO), VEGF, and GM-CSF in plasma and culture medium were determined. The number or activity of circulating EPCs and flow-mediated dilatation (FMD) in premenopausal women with or without HHcy were higher than those in postmenopausal women. However, no significant effect of HHcy on the number or activity of circulating EPCs in premenopausal women was observed. A similar alteration in NO level between the four groups was observed. There was a correlation between FMD and the number or activity of EPCs, as well as NO level in plasma or secretion by EPCs. For the first time, our findings illuminated the quantitive or qualitative alterations of circulating EPCs and endothelial function in premenopausal patients with HHcy are preserved, which was associated with retained NO production. The recuperated endothelial repair capacity is possibly the potential mechanism interpreting cardiovascular protection in premenopausal women with HHcy.
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http://dx.doi.org/10.1155/2020/5010243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657675PMC
October 2020

Impact of vitamin D on human embryo implantation-a prospective cohort study in women undergoing fresh embryo transfer.

Fertil Steril 2021 Mar 8;115(3):655-664. Epub 2020 Oct 8.

Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, People's Republic of China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, People's Republic of China; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany; Institute of Medical Diagnostics, Berlin, Germany. Electronic address:

Objective: To measure free and total 25-hydroxyvitamin D [25(OH)D] immediately before embryo transfer and analyze its association with early pregnancy outcome parameters such as biochemical pregnancy, implantation rate, and clinical pregnancy rates in women undergoing fresh embryo transfer after their first ovarian hyperstimulation.

Design: Prospective cohort study.

Setting: Academically affiliated private fertility center.

Patient(s): A total of 2,569 women undergoing fresh embryo transfer after ovarian hyperstimulation.

Interventions(s): None.

Main Outcome Measure(s): The study end points were biochemical pregnancy rate, implantation rate, clinical pregnancy rate, ectopic pregnancy rate, early miscarriages, and ongoing pregnancy rate. Free and total 25(OH)D concentrations were measured 1 day before embryo transfer.

Result(s): Total 25(OH)D correlated with free 25(OH)D. Total and free 25(OH)D serum concentrations were similar in those patients reaching and not reaching the study outcomes (biochemical pregnancy rate, implantation rate, clinical pregnancy rate, ectopic pregnancy rate, early miscarriages, and ongoing pregnancy rate). There was likewise no statistical difference when analyzing the frequency of all study outcomes in quintiles of either total or free 25(OH)D. In addition, the study population was divided into three groups according to the total vitamin D status based on clinical practice guideline. All outcomes were similar in women with adequate, insufficient, and deficient total 25(OH)D. Multiple linear regression analysis considering confounding likewise indicated no association of free or total vitamin D with any of the study outcomes.

Conclusion(s): Neither free nor total 25(OH)D concentration at embryo transfer was associated with successful embryo implantation in women undergoing fresh transfer after ovarian hyperstimulation.
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http://dx.doi.org/10.1016/j.fertnstert.2020.09.005DOI Listing
March 2021

Relationship between GFR, intact PTH, oxidized PTH, non-oxidized PTH as well as FGF23 in patients with CKD.

FASEB J 2020 11 22;34(11):15269-15281. Epub 2020 Sep 22.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.

Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are regulators of renal phosphate excretion and vitamin D metabolism. In chronic kidney disease (CKD), circulating FGF23 and PTH concentrations progressively increase as renal function declines. Oxidation of PTH at two methionine residues (positions 8 and 18) causes a loss of function. The impact of n-oxPTH and oxPTH on FGF23 synthesis, however, and how n-oxPTH and oxPTH concentrations are affected by CKD, is yet unknown. The effects of oxidized and non-oxidized PTH 1-34 on Fgf23 gene expression were analyzed in UMR106 osteoblast-like cells. Furthermore, we investigated the relationship between n-oxPTH and oxPTH, respectively, with FGF23 in two independent patients' cohorts (620 children with CKD and 600 kidney transplant recipients). While n-oxPTH stimulated Fgf23 mRNA synthesis in vitro, oxidation of PTH in particular at Met8 led to a markedly weaker stimulation of Fgf23. The effect was even stronger when both Met8 and Met18 were oxidized. In both clinical cohorts, n-oxPTH-but not oxPTH-was significantly associated with FGF23 concentrations, independent of known confounding factors. Moreover, with progressive deterioration of kidney function, intact PTH (iPTH) and oxPTH increased substantially, whereas n-oxPTH increased only moderately. In conclusion, n-oxPTH, but not oxPTH, stimulates Fgf23 gene expression. The increase in PTH with decreasing GFR is mainly due to an increase in oxPTH in more advanced stages of CKD.
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http://dx.doi.org/10.1096/fj.202000596RDOI Listing
November 2020

Non-oxidized PTH (n-oxPTH) is associated with graft loss in kidney transplant recipients.

Clin Chim Acta 2020 Sep 12;508:92-97. Epub 2020 May 12.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany; Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China; Institute of Medical Diagnostics, IMD, Berlin, Berlin, Germany. Electronic address:

Elevated parathyroid hormone (PTH) concentrations were reported to be associated with chronic renal allograft failure. However, measurements of PTH are challenging, because PTH can occur either as non-oxidized (n-ox) or oxidized (ox) PTH. Only n-ox PTH is a PTH receptor agonist. The intact PTH (iPTH) concentrations measured routinely in clinical practice, however, equals non-oxidized PTH (n-oxPTH) plus oxidized PTH (oxPTH). In CKD patients, the majority of the circulating PTH is oxidized. We measured iPTH, oxPTH and n-oxPTH at study entry in 600 kidney transplant recipients (KTRs). They were followed for graft loss for 3 years. Graft loss was defined as need for initiation of renal replacement therapy. Thirty-eight patients had graft loss during the 3 years follow-up. OxPTH correlated very well with iPTH (R = 0.997, p < 0.0001), whereas the correlation between n-oxPTH and iPTH was much weaker (R = 0.762, p < 0.0001). Compared to KTRs without graft loss, KTRs with graft loss had significantly higher levels of iPTH, oxPTH, and n-oxPTH (p < 0.0001 in all cases). After adjusting for confounding factors in cox proportional hazards analysis, only n-oxPTH, but not oxPTH neither iPTH, was significantly associated with graft loss (Hazard ratio (HR): 1.02, 95% CI: 1.01-1.03, p = 1.84 × 10). The very close correlation between oxPTH and iPTH measurements suggests that conventional iPTH measurements most likely describe oxidative stress rather than PTH bioactivity. Only non-oxidized PTH but not oxidized PTH nor intact PTH is associated with graft loss in stable kidney transplant recipients.
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http://dx.doi.org/10.1016/j.cca.2020.05.022DOI Listing
September 2020

Endostatin Is an Independent Risk Factor of Graft Loss after Kidney Transplant.

Am J Nephrol 2020 22;51(5):373-380. Epub 2020 Apr 22.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany,

Background: Endostatin is a 20-kDa C-terminal fragment of collagen XVIII, known for its ability to inhibit the proliferation of capillary endothelial cells. Previous studies suggested that circulating endostatin independently predicts incident chronic kidney disease. However, the impact of endostatin on graft loss level in kidney transplant recipients (KTRs) remains unknown.

Methods: We conducted a prospective observational cohort study in 574 maintenance KTRs. Patients were followed for kidney graft loss and all-cause mortality during a median follow-up of 48 months. Serum-, and urine-samples and clinical data were collected at baseline. Serum Endostatin concentration was analyzed by an ELISA.

Results: Among 574 patients, 37 patients had graft loss and 62 patients died. For graft loss, the optimal cut-off value based on receiver operating characteristics analysis (area under the curve 0.79, 95% CI 0.71-0.86, p < 0.001) of endostatin was 147.3 pmol/L. Kaplan-Meier curves revealed that higher serum endostatin concentrations positively correlated with graft loss (p < 0.001). Multivariable Cox regression analyses showed that baseline endostatin concentrations were significantly associated with graft loss after adjusting for graft loss risk factors (adjusted hazard ratio [HR] 8.34; 95% CI 2.19-31.72; p = 0.002). The adjusted HRs for classical graft loss risk factors such as baseline estimated glomerular filtration rate and urinary protein excretion were lower (1.91 and 5.44, respectively). In contrast to graft loss, baseline endostatin concentrations were not associated with all-cause mortality.

Conclusion: Increased serum endostatin at baseline is independently associated with the risk of graft loss in KTRs.
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http://dx.doi.org/10.1159/000507824DOI Listing
May 2021

Impact of maternal smoking associated lyso-phosphatidylcholine 20:3 on offspring brain development.

J Steroid Biochem Mol Biol 2020 05 15;199:105591. Epub 2020 Jan 15.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany; Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. Electronic address:

Maternal smoking during pregnancy affects fetal neurological development. Metabolomic studies in the general population suggest that smoking is associated with characteristic metabolic alterations. We investigated the association between the maternal smoking status, the fetal metabolome and head circumference at birth, as a surrogate parameter of brain development. 320 mother/newborn pairs of the Berlin Birth Cohort were investigated. Anthropometric parameters, including head circumference, of newborns of smoking mothers, former smoking mothers, and never smoking mothers were compared to assess the impact of maternal smoking behavior. Associations between maternal smoking behavior and 163 cord blood metabolites and associations between newborn head circumference and concentrations of smoking behavior related metabolites were analysed. Male newborns of smoking mothers had a reduced head circumference when compared with newborns from former smoking and never smoking mothers (p < 0.05). Using linear regression models corrected for established confounding factors, maternal smoking during pregnancy showed an independent association with head circumference (95% CI: -0.75~-0.41 cm, p = 2.45×10). In a stepwise linear regression model corrected for known confounding factors of brain growth lyso-phosphatidylcholine 20:3 (95% CI: 6.68~39.88 cm, p = 4.62×10) was associated with head circumference in male offspring only. None of the metabolites were associated with head circumference of female newborns. In conclusion, maternal smoking during pregnancy impacted on male offspring's development including brain development. The smoking related metabolite lyso-phosphatidylcholine 20:3 was associated with head circumference of male offspring.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105591DOI Listing
May 2020

The SGLT2 Inhibitor Empagliflozin Might Be a New Approach for the Prevention of Acute Kidney Injury.

Kidney Blood Press Res 2019 2;44(2):149-157. Epub 2019 Apr 2.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.

Three randomized control trials (Canagliflozin Cardiovascular Assessment Study, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME], and Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 [DECLARE-TIMI 58]) showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally developed as glucose-lowering drugs, are associated with a lower rate of adverse renal outcomes, such as need for renal replacement therapy, doubling of serum creatinine, and loss of glomerular filtration rate (GFR) compared to those in placebo groups. Besides, canagliflozin and empagliflozin also showed a lower risk of progression to macroalbuminuria. The EMPA-REG OUTCOME trial and DECLARE-TIMI 58 trial also indicated that these SGLT2 inhibitors might have beneficial effects on the prevention of acute kidney injury. The United States Food and Drug Administration (FDA) warned of the risk of acute kidney injury for canagliflozin and dapagliflozin. We compared canagliflozin, empagliflozin, and dapagliflozin with respect to chemical structure and pharmacological properties, to explain the observed differences in preventing acute kidney injury, and put forward the hypotheses of the potential mechanisms of different effects of SGLT2 inhibitors on acute kidney injury. Given the raising clinical use of SGLT2 inhibitors, our review should stimulate further basic science and clinical studies in order to definitively understand the role of SGLT2 inhibitors in acute kidney injury. A weakness of the clinical data obtained so far is the fact that the statements concerning acute kidney injury are just based on safety data - mainly creatine measurements. However, given the mode of action of SGLT2 blockers, initiation of a therapy with a SGLT2 blocker will cause an increase of creatine because of its effects on the tubuloglomerular feedback mechanisms/glomerular hemodynamics like RAAS blocking agents do. To really understand the potential effects of SGLT2 inhibitors, we need preclinical and clinical SGLT2 inhibitor studies focusing on all aspects of acute kidney injury - not just changes in GFR biomarkers.
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http://dx.doi.org/10.1159/000498963DOI Listing
December 2019

N-Acetylcysteine Suppresses LPS-Induced Pathological Angiogenesis.

Cell Physiol Biochem 2018 27;49(6):2483-2495. Epub 2018 Sep 27.

Division of Histology and Embryology, Internaitional Joint Laboratory for Embryonic Development & Prenatal Medicine, Medical College, Jinan University, Guangzhou, China.

Background/aims: Angiogenesis is a key feature during embryo development but is also part of the pathogenesis of cancer in adult life. Angiogenesis might be modulated by inflammation.

Methods: We established an angiogenesis model in chick chorioallantoic membrane (CAM) induced by the exposure of lipopolysaccharide (LPS), and analyzed the effects of the antioxidant N-acetylcysteine (NAC) on angiogenesis in this model as well as on the expression of key genes known to involved in the regulation of angiogenesis.

Results: Treatment with NAC was able to normalize LPS induced angiogenesis and restore the LPS-induced damage of vascular epithelium in chick CAM. Using quantitative PCR, we showed that NAC administration normalized the LPS induced expression of Keap1-Nrf2 signaling and oxidative stress key enzyme gene expressions (SOD, GPx and YAP1).

Conclusion: We established a LPS-induced angiogenesis model in chick CAM. NAC administration could effectively inhibit LPS-induced angiogenesis and restore the integrity of endothelium on chick CAM. LPS exposure caused an increased expression of genes involved in oxidative stress in chick CAM. NAC administration could abolish this effect.
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http://dx.doi.org/10.1159/000493874DOI Listing
October 2018

Lipopolysaccharides (LPS) Induced Angiogenesis During Chicken Embryogenesis is Abolished by Combined ETA/ETB Receptor Blockade.

Cell Physiol Biochem 2018 10;48(5):2084-2090. Epub 2018 Aug 10.

International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, China.

Background/aims: Angiogenesis plays a key role during embryonic development. The vascular endothelin (ET) system is involved in the regulation of angiogenesis. Lipopolysaccharides (LPS) could induce angiogenesis. The effects of ET blockers on baseline and LPS-stimulated angiogenesis during embryonic development remain unknown so far.

Methods: The blood vessel density (BVD) of chorioallantoic membranes (CAMs), which were treated with saline (control), LPS, and/or BQ123 and the ETB blocker BQ788, were quantified and analyzed using an IPP 6.0 image analysis program. Moreover, the expressions of ET-1, ET-2, ET3, ET receptor A (ETRA), ET receptor B (ETRB) and VEGFR2 mRNA during embryogenesis were analyzed by semi-quantitative RT-PCR.

Results: All components of the ET system are detectable during chicken embryogenesis. LPS increased angiogenesis substantially. This process was completely blocked by the treatment of a combination of the ETA receptor blockers-BQ123 and the ETB receptor blocker BQ788. This effect was accompanied by a decrease in ETRA, ETRB, and VEGFR2 gene expression. However, the baseline angiogenesis was not affected by combined ETA/ETB receptor blockade.

Conclusion: During chicken embryogenesis, the LPS-stimulated angiogenesis, but not baseline angiogenesis, is sensitive to combined ETA/ETB receptor blockade.
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http://dx.doi.org/10.1159/000492547DOI Listing
September 2018

Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium.

PLoS One 2018 12;13(4):e0195828. Epub 2018 Apr 12.

Institute for Nutritional Science, University of Potsdam, Potsdam, Germany.

Background: The use of iodine-based contrast agents entails the risk of contrast induced nephropathy (CIN). Radiocontrast agents elicit the third most common cause of nephropathy among hospitalized patients, accounting for 11-12% of cases. CIN is connected with clinically significant consequences, including increased morbidity, prolonged hospitalization, increased risk of complications, potential need for dialysis, and increased mortality rate. The number of in-hospital examinations using iodine-based contrast media has been significantly increasing over the last decade. In order to protect patients from possible complications of such examinations, new biomarkers are needed that are able to predict a risk of contrast-induced nephropathy. Urinary and plasma cyclic guanosine monophosphate (cGMP) concentrations are influenced by renal function. Urinary cGMP is primarily of renal cellular origin. Therefore, we assessed if urinary cGMP concentration may predict major adverse renal events (MARE) after contrast media exposure during coronary angiography.

Methods: Urine samples were prospectively collected from non-randomized consecutive patients with either diabetes or preexisting impaired kidney function receiving intra-arterial contrast medium (CM) for emergent or elective coronary angiography at the Charité Campus Mitte, University Hospital Berlin. Urinary cGMP concentration in spot urine was analyzed 24 hours after CM exposure. Patients were followed up over 90 days for occurrence of death, initiation of dialysis, doubling of plasma creatinine concentration or MARE.

Results: In total, 289 consecutive patients were included into the study. Urine cGMP/creatinine ratio 24 hours before CM exposure expressed as mean±SD was predictive for the need of dialysis (no dialysis: 89.77±92.85 μM/mM, n = 277; need for dialysis: 140.3±82.90 μM/mM, n = 12, p = 0.008), death (no death during follow-up: 90.60±92.50 μM/mM, n = 280; death during follow-up: 169.88±81.52 μM/mM, n = 9; p = 0.002), and the composite endpoint MARE (no MARE: 86.02±93.17 μM/mM, n = 271; MARE: 146.64±74.68 μM/mM, n = 18, p<0.001) during the follow-up of 90 days after contrast media application. cGMP/creatinine ratio stayed significantly increased at values exceeding 120 μM/mM in patients who developed MARE, required dialysis or died.

Conclusions: Urinary cGMP/creatinine ratio ≥ 120 μM/mM before CM exposure is a promising biomarker for the need of dialysis and all-cause mortality 90 days after CM exposure in patients with preexisting renal impairment or diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195828PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896998PMC
July 2018

The prognostic value of circulating cell-free DNA in breast cancer: A meta-analysis.

Medicine (Baltimore) 2018 Mar;97(13):e0197

Department of Central Laboratory Department of Nephrology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, People's Republic of China.

Background: Circulating cell-free DNA (cfDNA) isolated from plasma or serum by noninvasive procedures can serve as a "liquid biopsy" and has potential as a biomarker for the tumor burden and survival prediction of breast cancer (BC). However, its prognostic value in patients with BC is currently under debate. The aim of this meta-analysis was to investigate the relationship between cfDNA and survival outcome.

Methods: We systematically searched PubMed, Embase, and Science Citation Index electronic databases for studies about the prognostic utility of cfDNA in patients with BC. The clinical characteristics, relapse/disease-free survival (RFS/DFS), and overall survival (OS) data were extracted from the eligible studies. The hazard ratios (HR) and 95% confidence intervals (CI) were calculated and pooled with a fixed-effects model using the Stata12.0 software. Subgroup and sensitivity analyses were also performed.

Results: This meta-analysis included a total of 10 eligible studies and 1127 patients with BC. The pooled HR with 95% CI showed strong associations between cfDNA and OS (HR = 2.41, 95% CI, 1.83-3.16) along with DFS/RFS (HR = 2.73, 95% CI, 2.04-3.67) in patients with BC. Although publication bias was found in the studies regarding RFS/DFS, further trim and fill analysis revealed that the adjusted HR would be 2.53 (95% CI, 1.83-3.51), which is close to the original HR. Subgroup analyses confirmed the role of cfDNA as a strong prognostic marker in patients with BC, regardless of cfDNA analysis, sampling time, sample source, detection method, tumor stage, sample size, or area.

Conclusions: Our meta-analysis indicates that cfDNA is a strong predictive and prognostic marker in patients with BC.
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http://dx.doi.org/10.1097/MD.0000000000010197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895387PMC
March 2018

Cord Blood Lysophosphatidylcholine 16: 1 is Positively Associated with Birth Weight.

Cell Physiol Biochem 2018 29;45(2):614-624. Epub 2018 Jan 29.

Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Germany.

Background/aims: Impaired birth outcomes, like low birth weight, have consistently been associated with increased disease susceptibility to hypertension in later life. Alterations in the maternal or fetal metabolism might impact on fetal growth and influence birth outcomes. Discerning associations between the maternal and fetal metabolome and surrogate parameters of fetal growth could give new insight into the complex relationship between intrauterine conditions, birth outcomes, and later life disease susceptibility.

Methods: Using flow injection tandem mass spectrometry, targeted metabolomics was performed in serum samples obtained from 226 mother/child pairs at delivery. Associations between neonatal birth weight and concentrations of 163 maternal and fetal metabolites were analyzed.

Results: After FDR adjustment using the Benjamini-Hochberg procedure lysophosphatidylcholines (LPC) 14: 0, 16: 1, and 18: 1 were strongly positively correlated with birth weight. In a stepwise linear regression model corrected for established confounding factors of birth weight, LPC 16: 1 showed the strongest independent association with birth weight (CI: 93.63 - 168.94; P = 6.94×10-11 ). The association with birth weight was stronger than classical confounding factors such as offspring sex (CI: -258.81- -61.32; P = 0.002) and maternal smoking during pregnancy (CI: -298.74 - -29.51; P = 0.017).

Conclusions: After correction for multiple testing and adjustment for potential confounders, LPC 16: 1 showed a very strong and independent association with birth weight. The underlying molecular mechanisms linking fetal LPCs with birth weight need to be addressed in future studies.
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http://dx.doi.org/10.1159/000487118DOI Listing
March 2018

Prolonged Ocular Retention of Mucoadhesive Nanoparticle Eye Drop Formulation Enables Treatment of Eye Diseases Using Significantly Reduced Dosage.

Mol Pharm 2016 09 8;13(9):2897-905. Epub 2016 Aug 8.

Department of Chemical Engineering, University of Waterloo , Waterloo, Canada.

Eye diseases, such as dry eye syndrome, are commonly treated with eye drop formulations. However, eye drop formulations require frequent dosing with high drug concentrations due to poor ocular surface retention, which leads to poor patient compliance and high risks of side effects. We developed a mucoadhesive nanoparticle eye drop delivery platform to prolong the ocular retention of topical drugs, thus enabling treatment of eye diseases using reduced dosage. Using fluorescent imaging on rabbit eyes, we showed ocular retention of the fluorescent dye delivered through these nanoparticles beyond 24 h while free dyes were mostly cleared from the ocular surface within 3 h after administration. Utilizing the prolonged retention of the nanoparticles, we demonstrated effective treatment of experimentally induced dry eye in mice by delivering cyclosporin A (CsA) bound to this delivery system. The once a week dosing of 0.005 to 0.01% CsA in NP eye drop formulation demonstrated both the elimination of the inflammation signs and the recovery of ocular surface goblet cells after a month. Thrice daily administration of RESTASIS on mice only showed elimination without recovering the ocular surface goblet cells. The mucoadhesive nanoparticle eye drop platform demonstrated prolonged ocular surface retention and effective treatment of dry eye conditions with up to 50- to 100-fold reduction in overall dosage of CsA compared to RESTASIS, which may significantly reduce side effects and, by extending the interdosing interval, improve patient compliance.
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http://dx.doi.org/10.1021/acs.molpharmaceut.6b00445DOI Listing
September 2016

Density functional theory studies on hydroxylamine mechanism of cyclohexanone ammoximation on titanium silicalite-1 catalyst.

J Mol Model 2013 Jun 31;19(6):2217-24. Epub 2013 Jan 31.

Department of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Nankai District, Wei Jin Road 92, Tianjin 300072, China.

The hydroxylamine mechanism of cyclohexanone ammoximation on defective titanium active site of titanium silicalite-1 (TS-1) was simulated using two-layer ONIOM (M062X/6-31G**:PM6) method. A new energy favorable reaction route was found, which contained two parts: (1) the catalytic oxidation of adsorbed NH3 to form hydroxylamine using the Ti-OOH as an active oxidant formed by reacting H2O2 with the defective Ti active site; (2) the subsequent noncatalytic oximation of desorbed hydroxylamine and cyclohexanone out of TS-1 pores to form cyclohexanone oxime. In the catalytic formation of hydroxylamine on the Ti active site of TS-1, the proposed mechanism of two-step single-proton transfer aided by a lattice oxygen atom bonded to Ti atom need a lower reaction energy than the mechanism proposed before. In the subsequent noncatalytic oximation of hydroxylamine and cyclohexanone, which contained two elementary reaction steps in total, the mechanisms of one-step double-proton transfer in the first elementary reaction step and the subsequent one-step three-proton transfer for the second elementary reaction step were proposed, in which the solvent water molecules played a very important role in assisting and stabilizing the proton transfer processes.
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http://dx.doi.org/10.1007/s00894-013-1768-1DOI Listing
June 2013

Proliposomes for oral delivery of dehydrosilymarin: preparation and evaluation in vitro and in vivo.

Acta Pharmacol Sin 2011 Jul 13;32(7):973-80. Epub 2011 Jun 13.

Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China.

Aim: To formulate proliposomes with a polyphase dispersed system composed of soybean phospholipids, cholesterol, isopropyl myristate and sodium cholate to improve the oral bioavailability of dehydrosilymarin, an oxidized form of herbal drug silymarin.

Methods: Dehydrosilymarin was synthesized from air oxidation of silymarin in the presence of pyridine, and proliposomes were prepared by a film dispersion-freeze drying method. Morphological characterization of proliposomes was observed using a transmission electron microscope. Particle size and encapsulation efficiency of proliposomes were measured. The in vitro release of dehydrosilymarin from suspension and proliposomes was evaluated. The oral bioavailability of dehydrosilymarin suspension and proliposomes was investigated in rabbits.

Results: The proliposomes prepared under the optimum conditions were spherical and smooth with a mean particle size in the range of 7 to 50 nm. Encapsulation efficiency was 81.59%±0.24%. The in vitro accumulative release percent of dehydrosilymarinloaded proliposomes was stable, which was slow in pH 1.2, and increased continuously in pH 6.8, and finally reached 86.41% at 12 h. After oral administration in rabbits, the relative bioavailability of proliposomes versus suspension in rabbits was 228.85%.

Conclusion: Proliposomes may be a useful vehicle for oral delivery of dehydrosilymarin, a drug poorly soluble in water.
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http://dx.doi.org/10.1038/aps.2011.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003120PMC
July 2011

Preparation and effects of 2,3-dehydrosilymarin, a promising and potent antioxidant and free radical scavenger.

J Pharm Pharmacol 2011 Feb 18;63(2):238-44. Epub 2010 Nov 18.

Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, China.

Objectives: Silymarin or silybin has been effectively used for treating liver diseases and acute liver injury partly due to its antioxidant activity. In this study, 2,3-dehydrosilymarin, a compound exhibiting remarkable antiradical/antioxidant activity, was prepared from silymarin for the first time. The solubility, radical scavenging capacity and liver protecting activity of 2,3-dehydrosilymarin were studied and compared with silybin, dehydrosilybin and silymarin.

Methods: The structures of its main components were verified by ultra-performance liquid chromatography/mass spectrometry (UPLC-MS) and other spectral analysis. In addition, a rapid screening method, online high-performance liquid chromatography/1,1-dipheny1-2-picrylhydrazyl (HPLC-DPPH) system, was developed for identifying the individual antioxidants in 2,3-dehydrosilymarin.

Key Findings: Both in-vitro and in-vivo results markedly proved that dehydrosilymarin has decent aqueous solubility and remarkable antiradical/antioxidation capacity. Moreover, 2,3-dehydrosilybin and 2,3-dehydrosilychristin were identified to be the two major active compounds contained in 2,3-dehydrosilymarin.

Conclusions: Our results suggest that 2,3-dehydrosilymarin may be a promising and potent alternative for inhibition of free radical and prevention of oxidation.
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http://dx.doi.org/10.1111/j.2042-7158.2010.01210.xDOI Listing
February 2011

Acid polysaccharide-induced amorphous calcium carbonate (ACC) films: colloidal nanoparticle self-organization process.

Langmuir 2009 Mar;25(5):3045-9

Fiber and Polymer Science Program, Department of Fiber Science and Apparel Design, Cornell University, Ithaca, New York 14853-4401, USA.

Amorphous calcium carbonate (ACC) plays important roles in biomineralization, and its synthesis in vitro has been of keen interest in the field of biomimetic materials. In this report, we describe the synthesis of ACC films using a novel acid polysaccharide, maleic chitosan, as an additive. We prepared the films by directly depositing them onto TEM grids and examined them using polarized optical microscopy (POM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) combined with selected area electron diffraction (SAED). This enabled us to examine their formation and mesostructure without introducing artifacts. We observed that, in the presence of maleic chitosan, the ACC films are formed through a particle buildup process, with aggregation and coalescence occurring simultaneously. Nanoparticles with a size of less than 10 nm appear to be the basic units responsible for such self-organization. We suggest that the acid polysaccharide plays an important role in forming and stabilizing these nanoparticles, and we propose a colloidal nanoparticle self-organization model to explain the formation of the ACC films.
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http://dx.doi.org/10.1021/la803541mDOI Listing
March 2009

The effect of an acute elevation of NEFA concentrations on glucagon-stimulated hepatic glucose output.

Am J Physiol Endocrinol Metab 2006 Sep 11;291(3):E449-59. Epub 2006 Apr 11.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.

To determine the effect of nonesterified fatty acids (NEFA) on glucagon action, glucagon was infused intraportally (1.65 ng.min(-1).kg(-1)) for 3 h into 18-h-fasted, pancreatic-clamped conscious dogs in the presence [NEFA + glucagon (GGN)] or absence (GGN) of peripheral Intralipid plus heparin infusion. Additionally, hyperglycemic (HG), hyperglycemic-hyperlipidemic (NEFA + HG), and glycerol plus glucagon (GLYC + GGN) controls were studied. Arterial plasma glucagon concentrations rose equally in GGN, NEFA + GGN, and GLYC + GGN but remained basal in hyperglycemic controls. Peripheral infusions of Intralipid and heparin increased arterial plasma NEFA concentrations equally in NEFA + GGN and NEFA + HG and did not change in other protocols. After 15 min, glucagon infusion resulted in a rapid, brief increase in net hepatic glycogenolysis (NHGLY, mg.min(-1).kg(-1)) of approximately 6.0 in GGN and GLYC + GGN but only increased by 3.8 +/- 1.3 in NEFA + GGN. Thus increases in NHGLY, and consequently net hepatic glucose output (NHGO), were blunted by 40%, with no difference between the groups in the last 2.5 h of the study. NHGO and NHGLY did not significantly change in HG and NEFA + HG. Net hepatic gluconeogenic flux did not change in GGN, GLYC + GGN, or HG. However, Intralipid and heparin infusion resulted in similar increases in net hepatic gluconeogenic flux in NEFA + GGN and NEFA + HG. Thus elevated NEFA limit the initial increase in glucagon-stimulated HGO by blunting glycogenolysis, without having any effect on the gluconeogenic or glycogenolytic contributions or NHGO thereafter.
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http://dx.doi.org/10.1152/ajpendo.00043.2006DOI Listing
September 2006

Insulin's direct effects on the liver dominate the control of hepatic glucose production.

J Clin Invest 2006 Feb;116(2):521-7

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

Insulin inhibits glucose production through both direct and indirect effects on the liver; however, considerable controversy exists regarding the relative importance of these effects. The first aim of this study was to determine which of these processes dominates the acute control of hepatic glucose production (HGP). Somatostatin and portal vein infusions of insulin and glucagon were used to clamp the pancreatic hormones at basal levels in the nondiabetic dog. After a basal sampling period, insulin infusion was switched from the portal vein to a peripheral vein. As a result, the arterial insulin level doubled and the hepatic sinusoidal insulin level was reduced by half. While the arterial plasma FFA level and net hepatic FFA uptake fell by 40-50%, net hepatic glucose output increased more than 2-fold and remained elevated compared with that in the control group. The second aim of this study was to determine the effect of a 4-fold rise in head insulin on HGP during peripheral hyperinsulinemia and hepatic insulin deficiency. Sensitivity of the liver was not enhanced by increased insulin delivery to the head. Thus, this study demonstrates that the direct effects of insulin dominate the acute regulation of HGP in the normal dog.
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http://dx.doi.org/10.1172/JCI27073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1359060PMC
February 2006

[The clinical analysis of free patellar implantation in repairing the defect of the knee of giant cell tumors].

Zhonghua Wai Ke Za Zhi 2004 Jun;42(12):754-6

Department of Orthopaedics, First Affiliated Hospital of China Medical University, Shenyang 110001, China.

Objective: To analysis the clinical effects of free patellar implantation in treating the defect of the knee joint after the excision of giant cell tumor in the distal femur and the proximal tibia.

Methods: If the giant cell tumor in the distal femur and the proximal tibia invaded the articular surface, we resected the condyle of femur or tibia including the tumor, dissociated the patella and placed it in the condyle horizontally to repair the articular surface. The cruciate ligament was reserved in all the patients. The condyle of femur or tibia was replaced by the anterior surface or the articular surface of the patella respectively. The implanted patella was fixed by the screw to the contralateral condyle, and the remaining defect was filled by autogenous cancellous illium.

Results: Nine patients were followed up 3 to 121 months, the average was 65 months. None of them recurred or metastated. The excellent and good rate of the functional evaluation of knee joints was 88.9%.

Conclusion: After resecting the condyle of femur or tibia including the tumors which invade the articular surface, we find that free patellar implantation is a suitable way to repair the defect of the knee.
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June 2004

Effects of hyperglycemia, glucagon, and epinephrine on renal glucose release in the conscious dog.

Metabolism 2004 Jul;53(7):933-41

Department of Molecular Physiology and Biophysics and Diabetes Research and Training Center, Vanderbilt University, Nashville, TN, USA.

The role of renal glucose production after an overnight fast and in response to different hormonal conditions has been debated. The aim of this study was to determine whether hyperglycemia, glucagon, or epinephrine can affect renal glucose production. In 18-hour fasted conscious dogs a pancreatic clamp initially fixed insulin and glucagon at basal levels, following which 1 of 4 protocols was instituted. In G+E glucagon (1.5 ng. kg(-1). min(-1); portally) and epinephrine (50 ng. kg(-1). min(-1); peripherally) were increased, in G glucagon was increased alone, in E epinephrine was increased alone, and in C neither were increased. In G, E, and C, glucose was infused to match the hyperglycemia in G+E (approximately 250 mg/dL). The average net renal glucose output during the last 2 hours was not different from the basal values in any group. Furthermore, the changes in unidirectional renal glucose production were not significantly different among groups. Therefore, after an overnight fast in the conscious dog, the kidneys do not significantly contribute to overall glucose production or respond to glucagon or epinephrine.
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http://dx.doi.org/10.1016/j.metabol.2004.01.018DOI Listing
July 2004

Rapid translocation of hepatic glucokinase in response to intraduodenal glucose infusion and changes in plasma glucose and insulin in conscious rats.

Am J Physiol Gastrointest Liver Physiol 2004 Apr 4;286(4):G627-34. Epub 2003 Dec 4.

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA.

The rate of liver glucokinase (GK) translocation from the nucleus to the cytoplasm in response to intraduodenal glucose infusion and the effect of physiological rises of plasma glucose and/or insulin on GK translocation were examined in 6-h-fasted conscious rats. Intraduodenal glucose infusion (28 mg.kg(-1).min(-1) after a priming dose at 500 mg/kg) elevated blood glucose levels (mg/dl) in the artery and portal vein from 90 +/- 3 and 87 +/- 3 to 154 +/- 4 and 185 +/- 4, respectively, at 10 min. At 120 min, the levels had decreased to 133 +/- 6 and 156 +/- 5, respectively. Plasma insulin levels (ng/ml) in the artery and the portal vein rose from 0.7 +/- 0.1 and 1.8 +/- 0.3 to 11.8 +/- 1.5 and 20.2 +/- 2.0 at 10 min, respectively, and 12.4 +/- 3.1 and 18.0 +/- 4.8 at 30 min, respectively. GK was rapidly exported from the nucleus as determined by measuring the ratio of the nuclear to the cytoplasmic immunofluorescence (N/C) of GK (2.9 +/- 0.3 at 0 min to 1.7 +/- 0.2 at 10 min, 1.5 +/- 0.1 at 20 min, 1.3 +/- 0.1 at 30 min, and 1.3 +/- 0.1 at 120 min). When plasma glucose (arterial; mg/dl) and insulin (arterial; ng/ml) levels were clamped for 30 min at 93 +/- 7 and 0.7 +/- 0.1, 81 +/- 5 and 8.9 +/- 1.3, 175 +/- 5 and 0.7 +/- 0.1, or 162 +/- 5 and 9.2 +/- 1.5, the N/C of GK was 3.0 +/- 0.5, 1.8 +/- 0.1, 1.5 +/- 0.1, and 1.2 +/- 0.1, respectively. The N/C of GK regulatory protein (GKRP) did not change in response to the intraduodenal glucose infusion or the rise in plasma glucose and/or insulin levels. The results suggest that GK but not GKRP translocates rapidly in a manner that corresponds with changes in the hepatic glucose balance in response to glucose ingestion in vivo. Additionally, the translocation of GK is induced by the postprandial rise in plasma glucose and insulin.
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http://dx.doi.org/10.1152/ajpgi.00218.2003DOI Listing
April 2004

Allosteric activators of glucokinase: potential role in diabetes therapy.

Science 2003 Jul;301(5631):370-3

Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.

Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.
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http://dx.doi.org/10.1126/science.1084073DOI Listing
July 2003