TY  - JOUR
A1  - Heunisch, Fabian
A1  - Chaykovska, Lyubov
A1  - von Einem, Gina
A1  - Alter, Markus
A1  - Dschietzig, Thomas
A1  - Kretschmer, Axel
A1  - Kellner, Karl-Heinz
A1  - Hocher, Berthold
T1  - ADMA predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus undergoing coronary angiography
JF  - Medicine
N2  - Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of the nitric oxide (NO)-synthase and a biomarker of endothelial dysfunction (ED). ED plays an important role in the pathogenesis of contrast-induced nephropathy (CIN). The aim of our study was to evaluate serum ADMA concentration as a biomarker of an acute renal damage during the follow-up of 90 days after contrast medium (CM) application. Blood samples were obtained from 330 consecutive patients with diabetes mellitus or mild renal impairment immediately before, 24 and 48 hours after the CM application for coronary angiography. The patients were followed for 90 days. The composite endpoints were major adverse renal events (MARE) defined as occurrence of death, initiation of dialysis, or a doubling of serum creatinine concentration. Overall, ADMA concentration in plasma increased after CM application, although, there was no differences between ADMA levels in patients with and without CIN. ADMA concentration 24 hours after the CM application was predictive for dialysis with a specificity of 0.889 and sensitivity of 0.653 at values higher than 0.71 mu mol/L (area under the curve: 0.854, 95% confidential interval: 0.767-0.941, P<0.001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. 24 hours after the CM application, ADMA concentration in plasma was predictive for MARE with a specificity of 0.833 and sensitivity of 0.636 at a value of more than 0.70 mu mol/L (area under the curve: 0.750, 95% confidence interval: 0.602-0.897, P=0.004). Multivariate logistic regression analysis confirmed that ADMA and anemia were significant predictors of MARE. Further analysis revealed that increased ADMA concentration in plasma was highly significant predictor of MARE in patients with CIN. Moreover, patients with CIN and MARE had the highest plasma ADMA levels 24 hours after CM exposure in our study cohort. The impact of ADMA on MARE was independent of such known CIN risk factors as anemia, pre-existing renal failure, pre-existing heart failure, and diabetes. ADMA concentration in plasma is a promising novel biomarker of major contrast-induced nephropathy-associated events 90 days after contrast media exposure.
KW  - asymmetric dimethylarginine (ADMA)
KW  - biomarkers of renal failure
KW  - contrast-induced nephropathy
Y1  - 2017
U6  - https://doi.org/10.1097/MD.0000000000006065
SN  - 0025-7974
SN  - 1536-5964
VL  - 96
IS  - 6
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Hocher, Berthold
T1  - Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy
JF  - Journal of Molecular Endocrinology
N2  - Diabetic nephropathy is one of the most frequent, devastating and costly complications of diabetes. The available therapeutic approaches are limited. Dipeptidyl peptidase type 4 (DPP-4) inhibitors represent a new class of glucose-lowering drugs that might also have reno-protective properties. DPP-4 exists in two forms: a plasma membranebound form and a soluble form, and can exert many biological actions mainly through its peptidase activity and interaction with extracellular matrix components. The kidneys have the highest DPP-4 expression level in mammalians. DPP-4 expression and urinary activity are up-regulated in diabetic nephropathy, highlighting its role as a potential target to manage diabetic nephropathy. Preclinical animal studies and some clinical data suggest that DPP-4 inhibitors decrease the progression of diabetic nephropathy in a blood pressure-and glucose-independent manner. Many studies reported that these reno-protective effects could be due to increased half-life of DPP-4 substrates such as glucagon-like peptide-1 (GLP-1) and stromal derived factor-1 alpha (SDF-1a). However, the underlying mechanisms are far from being completely understood and clearly need further investigations.
KW  - DPP-4
KW  - diabetic nephropathy
KW  - DPP-4 inhibitors
KW  - GLP-1 and SDF-1a
Y1  - 2017
U6  - https://doi.org/10.1530/JME-17-0005
SN  - 0952-5041
SN  - 1479-6813
VL  - 59
SP  - R1
EP  - R10
PB  - Bioscientifica LTD
CY  - Bristol
ER  - 
TY  - JOUR
A1  - Lu, Yong-Ping
A1  - Reichetzeder, Christoph
A1  - Prehn, Cornelia
A1  - von Websky, Karoline
A1  - Slowinski, Torsten
A1  - Chen, You-Peng
A1  - Yin, Liang-Hong
A1  - Kleuser, Burkhard
A1  - Yang, Xue-Song
A1  - Adamski, Jerzy
A1  - Hocher, Berthold
T1  - Fetal serum metabolites are independently associated with Gestational diabetes mellitus
JF  - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology
N2  - Background/Aims: Gestational diabetes (GDM) might be associated with alterations in the metabolomic profile of affected mothers and their offspring. Until now, there is a paucity of studies that investigated both, the maternal and the fetal serum metabolome in the setting of GDM. Mounting evidence suggests that the fetus is not just passively affected by gestational disease but might play an active role in it. Metabolomic studies performed in maternal blood and fetal cord blood could help to better discern distinct fetal from maternal disease interactions. Methods: At the time of birth, serum samples from mothers and newborns (cord blood samples) were collected and screened for 163 metabolites utilizing tandem mass spectrometry. The cohort consisted of 412 mother/child pairs, including 31 cases of maternal GDM. Results: An initial non-adjusted analysis showed that eight metabolites in the maternal blood and 54 metabolites in the cord blood were associated with GDM. After Benjamini-Hochberg (BH) procedure and adjustment for confounding factors for GDM, fetal phosphatidylcholine acyl-alkyl C 32:1 and proline still showed an independent association with GDM. Conclusions: This study found metabolites in cord blood which were associated with GDM, even after adjustment for established risk factors of GDM. To the best of our knowledge, this is the first study demonstrating an independent association between fetal serum metabolites and maternal GDM. Our findings might suggest a potential effect of the fetal metabolome on maternal GDM. (c) 2018 The Author(s) Published by S. Karger AG, Basel
KW  - Gestational diabetes
KW  - Metabolomics
KW  - Phosphatidylcholine acyl-alkyl C 32:1
KW  - Proline
Y1  - 2018
U6  - https://doi.org/10.1159/000487119
SN  - 1015-8987
SN  - 1421-9778
VL  - 45
IS  - 2
SP  - 625
EP  - 638
PB  - Karger
CY  - Basel
ER  - 
TY  - JOUR
A1  - Lu, Yong-Ping
A1  - Reichetzeder, Christoph
A1  - Prehn, Cornelia
A1  - Yin, Liang-Hong
A1  - Yun, Chen
A1  - Zeng, Shufei
A1  - Chu, Chang
A1  - Adamski, Jerzy
A1  - Hocher, Berthold
T1  - Cord blood Lysophosphatidylcholine 16:1 is positively associated with birth weight
JF  - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology
N2  - 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 = 6.94x10(-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. (c) 2018 The Author(s) Published by S. Karger AG, Basel
KW  - Metabolomics
KW  - Lysophosphatidylcholine
KW  - Birth Weight
KW  - DOHaD
KW  - Hypertension
KW  - Type 2 Diabetes
Y1  - 2018
U6  - https://doi.org/10.1159/000487118
SN  - 1015-8987
SN  - 1421-9778
VL  - 45
IS  - 2
SP  - 614
EP  - 624
PB  - Karger
CY  - Basel
ER  - 
TY  - JOUR
A1  - Wang, Guang
A1  - Li, Pei-zhi
A1  - Zhang, Shi-yao
A1  - Zhong, Shan
A1  - Chu, Chang
A1  - Zeng, Shufei
A1  - Yan, Yu
A1  - Cheng, Xin
A1  - Chuai, Manli
A1  - Hocher, Berthold
A1  - Yang, Xuesong
T1  - Lipopolysaccharides (LPS) Induced Angiogenesis During Chicken Embryogenesis is Abolished by Combined ETA/ETB Receptor Blockade
JF  - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology
N2  - 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.
KW  - Lipopolysaccharides (LPS)
KW  - Angiogenesis
KW  - Chicken chorioallantoic membrane (CAM)
KW  - Endothelin (ET)
Y1  - 2018
U6  - https://doi.org/10.1159/000492547
SN  - 1015-8987
SN  - 1421-9778
VL  - 48
IS  - 5
SP  - 2084
EP  - 2090
PB  - Karger
CY  - Basel
ER  - 
TY  - GEN
A1  - Hocher, Berthold
A1  - Zeng, Shufei
T1  - Need for better PTH assays for clinical research and patient treatment
T2  - Clinical chemistry and laboratory medicine : journal of the Forum of the European Societies of Clinical Chemistry - the European Branch of the International Federation of Clinical Chemistry and Laboratory Medicine
Y1  - 2017
U6  - https://doi.org/10.1515/cclm-2017-0617
SN  - 1434-6621
SN  - 1437-4331
VL  - 56
IS  - 2
SP  - 183
EP  - 185
PB  - De Gruyter
CY  - Berlin
ER  - 
TY  - JOUR
A1  - Beaumont, Robin N.
A1  - Warrington, Nicole M.
A1  - Cavadino, Alana
A1  - Tyrrell, Jessica
A1  - Nodzenski, Michael
A1  - Horikoshi, Momoko
A1  - Geller, Frank
A1  - Myhre, Ronny
A1  - Richmond, Rebecca C.
A1  - Paternoster, Lavinia
A1  - Bradfield, Jonathan P.
A1  - Kreiner-Moller, Eskil
A1  - Huikari, Ville
A1  - Metrustry, Sarah
A1  - Lunetta, Kathryn L.
A1  - Painter, Jodie N.
A1  - Hottenga, Jouke-Jan
A1  - Allard, Catherine
A1  - Barton, Sheila J.
A1  - Espinosa, Ana
A1  - Marsh, Julie A.
A1  - Potter, Catherine
A1  - Zhang, Ge
A1  - Ang, Wei
A1  - Berry, Diane J.
A1  - Bouchard, Luigi
A1  - Das, Shikta
A1  - Hakonarson, Hakon
A1  - Heikkinen, Jani
A1  - Helgeland, Oyvind
A1  - Hocher, Berthold
A1  - Hofman, Albert
A1  - Inskip, Hazel M.
A1  - Jones, Samuel E.
A1  - Kogevinas, Manolis
A1  - Lind, Penelope A.
A1  - Marullo, Letizia
A1  - Medland, Sarah E.
A1  - Murray, Anna
A1  - Murray, Jeffrey C.
A1  - Njolstad, Pal R.
A1  - Nohr, Ellen A.
A1  - Reichetzeder, Christoph
A1  - Ring, Susan M.
A1  - Ruth, Katherine S.
A1  - Santa-Marina, Loreto
A1  - Scholtens, Denise M.
A1  - Sebert, Sylvain
A1  - Sengpiel, Verena
A1  - Tuke, Marcus A.
A1  - Vaudel, Marc
A1  - Weedon, Michael N.
A1  - Willemsen, Gonneke
A1  - Wood, Andrew R.
A1  - Yaghootkar, Hanieh
A1  - Muglia, Louis J.
A1  - Bartels, Meike
A1  - Relton, Caroline L.
A1  - Pennell, Craig E.
A1  - Chatzi, Leda
A1  - Estivill, Xavier
A1  - Holloway, John W.
A1  - Boomsma, Dorret I.
A1  - Montgomery, Grant W.
A1  - Murabito, Joanne M.
A1  - Spector, Tim D.
A1  - Power, Christine
A1  - Jarvelin, Marjo-Ritta
A1  - Bisgaard, Hans
A1  - Grant, Struan F. A.
A1  - Sorensen, Thorkild I. A.
A1  - Jaddoe, Vincent W.
A1  - Jacobsson, Bo
A1  - Melbye, Mads
A1  - McCarthy, Mark I.
A1  - Hattersley, Andrew T.
A1  - Hayes, M. Geoffrey
A1  - Frayling, Timothy M.
A1  - Hivert, Marie-France
A1  - Felix, Janine F.
A1  - Hypponen, Elina
A1  - Lowe, William L.
A1  - Evans, David M.
A1  - Lawlor, Debbie A.
A1  - Feenstra, Bjarke
A1  - Freathy, Rachel M.
T1  - Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics
JF  - Human molecular genetics
N2  - Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P< 5 x 10(-8). In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
Y1  - 2018
U6  - https://doi.org/10.1093/hmg/ddx429
SN  - 0964-6906
SN  - 1460-2083
VL  - 27
IS  - 4
SP  - 742
EP  - 756
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - GEN
A1  - Reichetzeder, Christoph
A1  - Hocher, Berthold
T1  - DPP4 inhibition prevents AKI
T2  - Oncotarget
KW  - acute kidney injury
KW  - DPP-4 inhibitors
KW  - ischemia reperfusion injury
KW  - gliptins
KW  - Dipeptidyl peptidase IV
Y1  - 2017
U6  - https://doi.org/10.18632/oncotarget.20212
SN  - 1949-2553
VL  - 8
SP  - 64655
EP  - 64656
PB  - Impact Journals LLC
CY  - Orchard Park
ER  - 
TY  - GEN
A1  - Hocher, Berthold
A1  - Zeng, Shufei
T1  - Clear the fog around parathyroid hormone assays
BT  - what do iPTH assays really measure?
T2  - Clinical journal of the American Society of Nephrology
KW  - Assays
KW  - Biological Assay
KW  - CKD
KW  - oxidative stress
KW  - PTH
Y1  - 2018
U6  - https://doi.org/10.2215/CJN.01730218
SN  - 1555-9041
SN  - 1555-905X
VL  - 13
IS  - 4
SP  - 524
EP  - 526
PB  - American Society of Nephrology
CY  - Washington
ER  - 
TY  - JOUR
A1  - Chaykovska, Lyubov
A1  - Heunisch, Fabian
A1  - von Einem, Gina
A1  - Hocher, Carl-Friedrich
A1  - Tsuprykov, Oleg
A1  - Pavkovic, Mira
A1  - Sandner, Peter
A1  - Kretschmer, Axel
A1  - Chu, Chang
A1  - Elitok, Saban
A1  - Stasch, Johannes-Peter
A1  - Hocher, Berthold
T1  - Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium
JF  - PLoS one
N2  - 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 Charite 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 mu M/mM, n = 277; need for dialysis: 140.3 +/- 82.90 mu M/mM, n = 12, p = 0.008), death (no death during follow-up: 90.60 +/- 92.50 mu M/mM, n = 280; death during follow-up: 169.88 +/- 81.52 mu M/mM, n = 9; p = 0.002), and the composite endpoint MARE (no MARE: 86.02 +/- 93.17 mu M/mM, n = 271; MARE: 146.64 +/- 74.68 mu M/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 pM/mM in patients who developed MARE, required dialysis or died. Conclusions Urinary cGMP/creatinine ratio >= 120 mu M/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.
Y1  - 2018
U6  - https://doi.org/10.1371/journal.pone.0195828
SN  - 1932-6203
VL  - 13
IS  - 4
PB  - PLoS
CY  - San Fransisco
ER  - 
TY  - JOUR
A1  - Bär, Ludmilla
A1  - Feger, Martina
A1  - Fajol, Abul
A1  - Klotz, Lars-Oliver
A1  - Zeng, Shufei
A1  - Lang, Florian
A1  - Hocher, Berthold
A1  - Föller, Michael
T1  - Insulin suppresses the production of fibroblast growth factor 23 (FGF23)
JF  - Proceedings of the National Academy of Sciences of the United States of America
N2  - Fibroblast growth factor 23 (FGF23) is produced by bone cells and regulates renal phosphate and vitamin D metabolism, as well as causing left ventricular hypertrophy. FGF23 deficiency results in rapid aging, whereas high plasma FGF23 levels are found in several disorders, including kidney or cardiovascular diseases. Regulators of FGF23 production include parathyroid hormone (PTH), calcitriol, dietary phosphate, and inflammation. We report that insulin and insulin-like growth factor 1 (IGF1) are negative regulators of FGF23 production. In UMR106 osteoblast-like cells, insulin and IGF1 down-regulated FGF23 production by inhibiting the transcription factor forkhead box protein O1 (FOXO1) through phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt signaling. Insulin deficiency caused a surge in the serum FGF23 concentration in mice, which was reversed by administration of insulin. In women, a highly significant negative correlation between FGF23 plasma concentration and increase in plasma insulin level following an oral glucose load was found. Our results provide strong evidence that insulin/IGF1dependent PI3K/PKB/Akt/FOXO1 signaling is a powerful suppressor of FGF23 production in vitro as well as in mice and in humans.
KW  - PI3K
KW  - PKB/Akt
KW  - Klotho
KW  - phosphate
Y1  - 2018
U6  - https://doi.org/10.1073/pnas.1800160115
SN  - 0027-8424
VL  - 115
IS  - 22
SP  - 5804
EP  - 5809
PB  - National Acad. of Sciences
CY  - Washington
ER  - 
TY  - JOUR
A1  - Tsuprykov, Oleg
A1  - Chen, Xin
A1  - Hocher, Carl-Friedrich
A1  - Skoblo, Roman
A1  - Yin, Lianghong
A1  - Hocher, Berthold
T1  - Why should we measure free 25(OH) vitamin D?
JF  - The Journal of Steroid Biochemistry and Molecular Biology
N2  - Vitamin D, either in its D-2 or D-3 form, is essential for normal human development during intrauterine life, kidney function and bone health. Vitamin D deficiency has also been linked to cancer development and some auto immune diseases. Given this huge impact of vitamin Don human health, it is important for daily clinical practice and clinical research to have reliable tools to judge on the vitamin D status. The major circulating form of vitamin D is 25-hydroxyvitamin D (25(OH)D), although it is not the most active metabolite, the concentrations of total 25-hydroxyvitamin D in the serum are currently routinely used in clinical practice to assess vitamin D status. In the circulation, vitamin D - like other steroid hormones - is bound tightly to a special carrier - vitamin D-binding protein (DBP). Smaller amounts are bound to blood proteins - albumin and lipoproteins. Only very tiny amounts of the total vitamin D are free and potentially biologically active. Currently used vitamin D assays do not distinguish between the three forms of vitamin D - DBP-bound vitamin D, albumin-bound vitamin D and free, biologically active vitamin D. Diseases or conditions that affect the synthesis of DBP or albumin thus have a huge impact on the amount of circulating total vitamin D. DBP and albumin are synthesized in the liver, hence all patients with an impairment of liver function have alterations in their total vitamin D blood concentrations, while free vitamin D levels remain mostly constant. Sex steroids, in particular estrogens, stimulate the synthesis of DBP. This explains why total vitamin D concentrations are higher during pregnancy as compared to nonpregnant women, while the concentrations of free vitamin D remain similar in both groups of women. The vitamin D-DBP as well as vitamin D-albumin complexes are filtered through the glomeruli and re-uptaken by megalin in the proximal tubule. Therefore, all acute and chronic kidney diseases that are characterized by a tubular damage, are associated with a loss of vitamin D-DBP complexes in the urine. Finally, the gene encoding DBP protein is highly polymorphic in different human racial groups. In the current review, we will discuss how liver function, estrogens, kidney function and the genetic background might influence total circulating vitamin D levels and will discuss what vitamin D metabolite is more appropriate to measure under these conditions: free vitamin D or total vitamin D.
KW  - 1,25(OH)(2) vitamin D
KW  - Bioavailable vitamin D
KW  - Calculated free 25(OH) vitamin D
KW  - Free 25(OH) vitamin D
KW  - Free vitamin D
KW  - Directly measured free vitamin D
KW  - Genetic polymorphism
KW  - Total 25(OH) vitamin D
KW  - Vitamin D-binding protein
Y1  - 2107
U6  - https://doi.org/10.1016/j.jsbmb.2017.11.014
SN  - 0960-0760
VL  - 180
SP  - 87
EP  - 104
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - JOUR
A1  - von Websky, Karoline
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Reichetzeder, Christoph
A1  - Tsuprykov, Oleg
A1  - Hocher, Berthold
T1  - Impact of vitamin D on pregnancy-related disorders and on offspring outcome
JF  - The Journal of Steroid Biochemistry and Molecular Biology
N2  - Observational studies from all over the world continue to find high prevalence rates of vitamin D insufficiency and deficiency in many populations, including pregnant women. Beyond its classical function as a regulator of calcium and phosphate metabolism, vitamin D elicits numerous effects in the human body. Current evidence highlights a vital role of vitamin D in mammalian gestation. During pregnancy, adaptations in maternal vitamin D metabolism lead to a physiologic increase of vitamin D levels, mainly because of an increased renal production, although other potential sources like the placenta are being discussed. A sufficient supply of mother and child with calcium and vitamin D during pregnancy ensures a healthy bone development of the fetus, whereas lack of either of these nutrients can lead to the development of rickets in the child. Moreover, vitamin D insufficiency during pregnancy has consistently been associated with adverse maternal and neonatal pregnancy outcomes. In multitudinous studies, low maternal vitamin D status was associated with a higher risk for pre-eclampsia, gestational diabetes mellitus and other gestational diseases. Likewise, several negative consequences for the fetus have been reported, including fetal growth restriction, increased risk of preterm birth and a changed susceptibility for later-life diseases. However, study results are diverging and causality has not been proven so far. Meta-analyses on the relationship between maternal vitamin D status and pregnancy outcomes revealed a wide heterogeneity of studied populations and the applied methodology in vitamin D assessment. Until today, clinical guidelines for supplementation cannot be based on high-quality evidence and it is not clear if the required intake for pregnant women differs from non-pregnant women. Long-term safety data of vitamin D supplementation in pregnant women has not been established and overdosing of vitamin D might have unfavorable effects, especially in mothers and newborns with mutations of genes involved in vitamin D metabolism. Reliable data from large observational and interventional randomized control trials are urgently needed as a basis for any detailed and safe recommendations for supplementation in the general population and, most importantly, in pregnant women. This is of utmost importance, as ensuring a sufficient vitamin D-supply of mother and child implies a great potential for the prevention of birth complications and development of diseases.
KW  - Vitamin D deficiency
KW  - Free vitamin D
KW  - Vitamin D binding protein
KW  - Epigenetics
KW  - DNA methylation
KW  - Single nucleotide polymorphism
KW  - Preeclampsia
KW  - Gestational diabetes mellitus
KW  - Small for gestational age
KW  - Long term health
Y1  - 2018
U6  - https://doi.org/10.1016/j.jsbmb.2017.11.008
SN  - 0960-0760
VL  - 180
SP  - 51
EP  - 64
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Tsuprykov, Oleg
A1  - Buse, Claudia
A1  - Skoblo, Roman
A1  - Haq, Afrozul
A1  - Hocher, Berthold
T1  - Reference intervals for measured and calculated free 25-hydroxyvitamin D in normal pregnancy
JF  - The Journal of Steroid Biochemistry and Molecular Biology
N2  - The determination of free 25-hydroxyvitamin D (25(OH)D) as compared to the analysis of total 25-hydroxyvitamin D might reflect better the vitamin D status during pregnancy, since vitamin D-binding protein (DBP) concentrations increase throughout pregnancy and the vast majority of 25(OH)D is tightly bound to DBP thus strongly influencing total 25(OH)D. The concentration of the biologically active free 25(OH)D - on the other hand - is much less dependent on the DBP concentrations. The study was conducted in May-June 2016 in 368 Caucasian pregnant healthy women - residents of Northeastern Germany. Free 25(OH)D was either measured directly by commercial ELISA kit or assessed by calculation via total 25(OH)D, DBP, and albumin serum concentrations. Regardless of the detection method, free 25(OH)D lowers in the 3rd trimester comparing to the 1st trimester (by 12% and 21%, p < 0.05 and p < 0.001, for measured and calculated free 25(OH)D, respectively), whereas total 25(OH)D was not decreased in late pregnancy. DBP rises with gestational age. Total 25(OH)D was not correlated with serum calcium (p = 0.251), whereas free 25(OH)D was significantly (p = 0.007 for measured free 25(OH)D and p < 0.001 for calculated free 25(OH)D) positively correlated with calcium. All 25(OH) D isoforms were significantly negatively correlated with bone-specific alkaline phosphatase (BSAP), however the correlation strength was the lowest with total 25(OH)D (rho = -0.108, p = 0.038), whereas both measured and calculated free 25(OH)D revealed better associations with BSAP (rho = -0.203 and rho = -0.211 for measured and calculated free 25(OH)D, respectively, p < 0.001 for both). We established pregnancy trimester specific reference intervals for free measured and calculated 25(OH)D and DBP. Both measured and calculated free 25(OH)D showed better correlations with parameters of the endocrine vitamin D system (calcium and BSAP). Both ways of measuring free 25(OH)D in pregnant women are suitable as novel laboratory parameter for vitamin D status monitoring during human pregnancy and might replace in the future the routine total 25(OH)D assessment.
KW  - Measured free 25-hydroxyvitamin D
KW  - Calculated free 25-hydroxyvitamin D
KW  - Vitamin D-binding protein
KW  - Pregnancy
KW  - Reference intervals
Y1  - 2018
U6  - https://doi.org/10.1016/j.jsbmb.2018.03.005
SN  - 0960-0760
VL  - 181
SP  - 80
EP  - 87
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Luo, Ting
A1  - Chen, Xiaoyi
A1  - Zeng, Shufei
A1  - Guan, Baozhang
A1  - Hu, Bo
A1  - Meng, Yu
A1  - Liu, Fanna
A1  - Wong, Taksui
A1  - Lu, Yongpin
A1  - Yun, Chen
A1  - Hocher, Berthold
A1  - Yin, Lianghong
T1  - Bioinformatic identification of key genes and analysis of prognostic values in clear cell renal cell carcinoma
JF  - Oncology Letters
N2  - The present study aimed to identify new key genes as potential biomarkers for the diagnosis, prognosis or targeted therapy of clear cell renal cell carcinoma (ccRCC). Three expression profiles (GSE36895, GSE46699 and GSE71963) were collected from Gene Expression Omnibus. GEO2R was used to identify differentially expressed genes (DEGs) in ccRCC tissues and normal samples. The Database for Annotation, Visualization and Integrated Discovery was utilized for functional and pathway enrichment analysis. STRING v10.5 and Molecular Complex Detection were used for protein-protein interaction (PPI) network construction and module analysis, respectively. Regulation network analyses were performed with the WebGestal tool. UALCAN web-portal was used for expression validation and survival analysis of hub genes in ccRCC patients from The Cancer Genome Atlas (TCGA). A total of 65 up- and 164 downregulated genes were identified as DEGs. DEGs were enriched with functional terms and pathways compactly related to ccRCC pathogenesis. Seventeen hub genes and one significant module were filtered out and selected from the PPI network. The differential expression of hub genes was verified in TCGA patients. Kaplan-Meier plot showed that high mRNA expression of enolase 2 (ENO2) was associated with short overall survival in ccRCC patients (P=0.023). High mRNA expression of cyclin D1 (CCND1) (P<0.001), fms related tyrosine kinase 1 (FLT1) (P=0.004), plasminogen (PLG) (P<0.001) and von Willebrand factor (VWF) (P=0.008) appeared to serve as favorable factors in survival. These findings indicate that the DEGs may be key genes in ccRCC pathogenesis and five genes, including ENO2, CCND1, PLT1, PLG and VWF, may serve as potential prognostic biomarkers in ccRCC.
KW  - clear cell renal cell carcinoma
KW  - bioinformatics
KW  - differentially expressed genes
KW  - biomarkers
KW  - Kaplan-Meier plot
Y1  - 2018
U6  - https://doi.org/10.3892/ol.2018.8842
SN  - 1792-1074
SN  - 1792-1082
VL  - 16
IS  - 2
SP  - 1747
EP  - 1757
PB  - Spandidos publ LTD
CY  - Athens
ER  - 
TY  - JOUR
A1  - Li, Jian
A1  - Lu, Yong-Ping
A1  - Tsuprykov, Oleg
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Reichetzeder, Christoph
A1  - Tian, Mei
A1  - Zhang, Xiao Li
A1  - Zhang, Qin
A1  - Sun, Guo-Ying
A1  - Guo, Jingli
A1  - Gaballa, Mohamed Mahmoud Salem Ahmed
A1  - Peng, Xiao-Ning
A1  - Lin, Ge
A1  - Hocher, Berthold
T1  - Folate treatment of pregnant rat dams abolishes metabolic effects in female offspring induced by a paternal pre-conception unhealthy diet
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - Aims/hypothesis Paternal high-fat diet prior to mating programmes impaired glucose tolerance in female offspring. We examined whether the metabolic consequences in offspring could be abolished by folate treatment of either the male rats before mating or the corresponding female rats during pregnancy. Methods Male F0 rats were fed either control diet or high-fat, high-sucrose and high-salt diet (HFSSD), with or without folate, before mating. Male rats were mated with control-diet-fed dams. After mating, the F0 dams were fed control diet with or without folate during pregnancy.
KW  - Glucose tolerance
KW  - High-fat-sucrose-salt diet
KW  - Maternal folate treatment
KW  - Paternal programming
Y1  - 2018
U6  - https://doi.org/10.1007/s00125-018-4635-x
SN  - 0012-186X
SN  - 1432-0428
VL  - 61
IS  - 8
SP  - 1862
EP  - 1876
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Gao, Lin-rui
A1  - Wang, Guang
A1  - Zhang, Jing
A1  - Li, Shuai
A1  - Chuai, Manli
A1  - Bao, Yongping
A1  - Hocher, Berthold
A1  - Yang, Xuesong
T1  - High salt-induced excess reactive oxygen species production resulted in heart tube malformation during gastrulation
JF  - Journal of Cellular Physiology
N2  - An association has been proved between high salt consumption and cardiovascular mortality. In vertebrates, the heart is the first functional organ to be formed. However, it is not clear whether high-salt exposure has an adverse impact on cardiogenesis. Here we report high-salt exposure inhibited basement membrane breakdown by affecting RhoA, thus disturbing the expression of Slug/E-cadherin/N-cadherin/Laminin and interfering with mesoderm formation during the epithelial-mesenchymal transition(EMT). Furthermore, the DiI(+) cell migration trajectory in vivo and scratch wound assays in vitro indicated that high-salt exposure restricted cell migration of cardiac progenitors, which was caused by the weaker cytoskeleton structure and unaltered corresponding adhesion junctions at HH7. Besides, down-regulation of GATA4/5/6, Nkx2.5, TBX5, and Mef2c and up-regulation of Wnt3a/-catenin caused aberrant cardiomyocyte differentiation at HH7 and HH10. High-salt exposure also inhibited cell proliferation and promoted apoptosis. Most importantly, our study revealed that excessive reactive oxygen species(ROS)generated by high salt disturbed the expression of cardiac-related genes, detrimentally affecting the above process including EMT, cell migration, differentiation, cell proliferation and apoptosis, which is the major cause of malformation of heart tubes.
KW  - cardiac progenitor migration and differentiation
KW  - chick embryo
KW  - heart tube
KW  - high salt
KW  - reactive oxygen species
Y1  - 2018
U6  - https://doi.org/10.1002/jcp.26528
SN  - 0021-9541
SN  - 1097-4652
VL  - 233
IS  - 9
SP  - 7120
EP  - 7133
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Glosse, Philipp
A1  - Feger, Martina
A1  - Mutig, Kerim
A1  - Chen, Hong
A1  - Hirche, Frank
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Gaballa, Mohamed Mahmoud Salem Ahmed
A1  - Hocher, Berthold
A1  - Lang, Florian
A1  - Föller, Michael
T1  - AMP-activated kinase is a regulator of fibroblast growth factor 23 production
JF  - Kidney international : official journal of the International Society of Nephrology
N2  - Fibroblast growth factor 23 (FGF23) is a proteohormone regulating renal phosphate transport and vitamin D metabolism as well as inducing left heart hypertrophy. FGF23-deficient mice suffer from severe tissue calcification, accelerated aging and a myriad of aging-associated diseases. Bone cells produce FGF23 upon store-operated calcium ion entry (SOCE) through the calcium selective ion channel Orai1. AMP-activated kinase (AMPK) is a powerful energy sensor helping cells survive states of energy deficiency, and AMPK down-regulates Orai1. Here we investigated the role of AMPK in FGF23 production. Fgf23 gene transcription was analyzed by qRT-PCR and SOCE by fluorescence optics in UMR106 osteoblast-like cells while the serum FGF23 concentration and phosphate metabolism were assessed in AMPKa1-knockout and wild-type mice. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) down-regulated, whereas the AMPK inhibitor, dorsomorphin dihydrochloride (compound C) and AMPK gene silencing induced Fgf23 transcription. AICAR decreased membrane abundance of Orai1 and SOCE. SOCE inhibitors lowered Fgf23 gene expression induced by AMPK inhibition. AMPKa1-knockout mice had a higher serum FGF23 concentration compared to wild-type mice. Thus, AMPK participates in the regulation of FGF23 production in vitro and in vivo. The inhibitory effect of AMPK on FGF23 production is at least in part mediated by Orai1-involving SOCE.
KW  - calcium
KW  - FGF23
KW  - Klotho
KW  - Orai1
KW  - phosphate
KW  - parathyroid hormone
Y1  - 2018
U6  - https://doi.org/10.1016/j.kint.2018.03.006
SN  - 0085-2538
SN  - 1523-1755
VL  - 94
IS  - 3
SP  - 491
EP  - 501
PB  - Elsevier
CY  - New York
ER  - 
TY  - GEN
A1  - Tammen, Harald
A1  - Koemhoff, Martin
A1  - Mark, Michael
A1  - Hocher, Berthold
A1  - Delic, Denis
A1  - Hess, Rüdiger
A1  - von Eynatten, Maximilian
A1  - Klein, Thomas
T1  - Linagliptin treatment is associated with improved cobalamin (vitamin B-12) storage in mice and potentially in humans
T2  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
Y1  - 2018
SN  - 0012-186X
SN  - 1432-0428
VL  - 61
SP  - S252
EP  - S253
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Tao, Ting
A1  - Su, Qiongli
A1  - Xu, Simeng
A1  - Deng, Jun
A1  - Zhou, Sichun
A1  - Zhuang, Yu
A1  - Huang, Yanjun
A1  - He, Caimei
A1  - He, Shanping
A1  - Peng, Mei
A1  - Hocher, Berthold
A1  - Yang, Xiaoping
T1  - Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis
JF  - Journal of cellular physiology
N2  - Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c). We first discovered that PKM2 physically interacts with the SREBP-1c using biochemical approaches, and downregulation of PKM2 reduced the expression of SREBP-1c by inactivating the AKT/mTOR signaling pathway, which in turn directly suppressed the transcription of major lipogenic genes FASN to reduce tumor growths. Furthermore, either PKM2 inhibitor-Shikonin or FASN inhibitor-TVB-3166 alone induced a strong antiproliferative and anticolony forming effect in bladder cancer cell line. The combination of both inhibitors exhibits a super synergistic effect on blocking the bladder cancer cells growth. It provides a new target and scientific basis for the treatment of bladder cancer.
KW  - bladder cancer cells
KW  - FASN
KW  - p-AKT
KW  - PKM2
KW  - p-mTOR
KW  - SREBP-1c
Y1  - 2018
U6  - https://doi.org/10.1002/jcp.27129
SN  - 0021-9541
SN  - 1097-4652
VL  - 234
IS  - 3
SP  - 3088
EP  - 3104
PB  - Wiley
CY  - Hoboken
ER  -