Only bioactive forms of PTH (n-oxPTH and Met18(ox)-PTH) inhibit synthesis of sclerostin - evidence from in vitro and human studies.

Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis.

Both partial inactivation as well as activation of NF-κB signaling lead to hypertension and chronic kidney disease.

BACKGROUND AND HYPOTHESIS: Activation of NF-κB-signalling is key in the pathogenesis of chronic kidney diseases (CKD). However, a certain level of NF-κB activity is necessary to enable tissue repair. METHODS: To investigate the relationship between activated and inactivated NF-κB signaling on the pathogenesis of CKD using mouse models of NF-κB partial inactivation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into alanine) and activation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into serine). RESULTS: The density of CD3, CD8, CD68 positive cells, as well as the expression of IL-6, TRAF-1, and NAF-1 in the kidney tissues of NF-κBC59A mice were reduced, whereas an opposing pattern was observed in the NF-κBC59S mice. Blood pressure, kidney fibrosis (analyzed by PAS-, Masson trichrome-, and Sirius-Red-staining as well as α-SMA immunofluorescence), serum creatinine and urinary albumin-to-creatinine-ratio are markedly increased in NF-κB activated and inactivated mice compared to controls. Transmission electron microscopy indicated that the glomerular basement membrane was thicker in both NF-κBC59A and NF-κBC59S mice compared to wild-type mice. CONCLUSIONS: Using mice models with partially activated and inactivated NF-κB pathways suggests that there is an apparently U-shaped relationship between blood pressure, kidney function as well as morphology and the activation of the NF-κB pathway. A certain optimal activity of the NF-κB pathway seems to be important to maintain optimal kidney function and morphology.

Vitamin D binding protein correlate with estrogen increase after administration of human chorionic gonadotropin but do not affect ovulation, embryo, or pregnancy outcomes.

Background: Vitamin D binding protein (DBP) might increase substantially after ovarian stimulation and hence could be associated with IVF/ICSI outcomes because it determines the fraction of free bioavailable 25(OH) vitamin D. In this study, we aim to determine whether DBP is associated with E2 level after ovarian stimulation and IVF/ICSI outcomes. Design: Post-hoc analysis of a prospective observational cohort. Setting: Single-center study. Participants: 2569 women receiving embryo transfer. Intervention: None. Main outcome measures: The main outcomes were oocyte and embryo quality as well as pregnancy outcomes. Results: DBP concentration correlates with E2 on hCG day (=day of inducing ovulation with hCG; correlation coefficient r = 0.118, P<0.001) and E2 x-fold change to baseline level (r = 0.108, P<0.001). DBP is also positively correlated with total 25(OH)D (r = 0.689, R2 = 0.475, P<0.001) and inversely with free 25(OH)D (r=-0.424, R2=0.179, P<0.001), meaning that E2-stimulated DBP synthesis results in a decrease of free 25(OH)D during ovarian stimulation. However, such alteration does not affect IVF/ICSI outcomes when considering confounding factors, such as the number and quality of oocytes nor embryo quality as well as pregnancy outcomes. Conclusion: DBP concentration correlates with the degree of E2 increase after ovarian stimulation. DBP is also positively correlated with total 25(OH)D and inversely with free 25(OH)D, suggesting that the proportion of free 25(OH)D decreases during ovarian stimulation caused by E2-stimulated DBP synthesis. However, such alteration does not affect clinical IVF/ICSI outcomes.

Inverse association of prepregnancy systolic blood pressure and live birth rate in normotensive women undergoing in vitro fertilization/intracytoplasmic sperm injection.

OBJECTIVE: To explore whether maternal baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) affect pregnancy outcomes particularly in normotensive women (SBP, 90-139 mm Hg; DBP, 60-89 mm Hg) and hypertensive women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective cohort study. SETTING: Maximum care hospital for reproductive medicine. PATIENT(S): This study included 73,462 patients who underwent IVF/ICSI at the Reproductive and Genetic Hospital of CITIC-Xiangya between January 1, 2016, and November 30, 2020, selected on the basis of pre-established criteria. Analysis was limited to the first transfer cycle of the first stimulation cycle. INTERVENTION: Baseline SBP and DBP. MAIN OUTCOME MEASURE(S): The primary outcome focused on the live birth rate (LBR), with the secondary outcomes including clinical pregnancy rate, ectopic pregnancy rate, first-trimester miscarriage rate, second- or third-trimester fetal loss, and delivery/neonatal/maternal outcomes. Analytic methods included Poisson regression, linear regression, linear mixed-effect model, and restricted cubic spline analysis as appropriate. RESULT(S): For normotensive women, a 10-mm Hg increase in SBP was associated with an adjusted relative risk of 0.988 (95% confidence interval, 0.981-0.995) for live birth likelihood. However, DBP was not significantly associated with LBR after adjustments. The secondary outcomes indicated that increases in SBP and DBP were associated with higher risks of first-trimester miscarriage, gestational diabetes mellitus, and gestational hypertension in the normotensive subset. Sensitivity analyses confirmed these associations between SBP/DBP and LBR, consistent with the main findings even under stricter guidelines and after adjusting for multiple confounders. Subgroup analyses showed variation in the impact of blood pressure on LBR across different demographics and conditions. Consistent with earlier studies on blood pressure and birth outcomes, we found a 10-mm Hg increase in SBP was associated with a 5.4% (adjusted relative risk per 10 mm Hg, 0.946; 95% confidence interval, 0.907-0.986) reduction in LBR in the hypertensive subgroup. CONCLUSION(S): Systolic blood pressure impacted LBR outcomes in normotensive women who underwent IVF/ICSI, which suggests the need for reconsidering blood pressure management guidelines for reproductive-age women, focusing on reproductive health in addition to cardiovascular risk.

Periostin Predicts All-Cause Mortality in Male but Not Female End-Stage Renal Disease Patients on Hemodialysis.

INTRODUCTION: Periostin is a matricellular protein. Elevated serum concentrations of periostin have been reported in patients with various cardiovascular diseases, including heart failure. Patients with end-stage renal disease have a substantially increased risk for cardiovascular diseases. However, there is a lack of clinical studies to clarify the prognostic significance of systemic periostin on all-cause mortality in patients with end-stage renal disease on hemodialysis. METHODS: 313 stable end-stage renal disease patients were recruited and followed for 5 years concerning all-cause mortality. At baseline, we collected blood samples and clinical data. Serum periostin concentrations were measured using a certified ELISA. RESULTS: The optimal cut-off value for serum periostin regarding all-cause mortality, calculated through receiver operating characteristic analysis, was 777.5 pmol/L. Kaplan-Meier survival analysis using this cut-off value demonstrated that higher periostin concentrations are linked to higher all-cause mortality (log-rank test: p = 0.002). Subgroup analysis revealed that serum periostin concentrations only affected all-cause mortality in male but not in female patients (p = 0.002 in male patients and p = 0.474 in female patients). Multivariate Cox regression analyses, adjusted for confounding factors, likewise showed that elevated serum periostin concentrations were positively associated with all-cause mortality in male (p = 0.028) but not in female patients on hemodialysis (p = 0.313). CONCLUSION: Baseline serum periostin is an independent risk factor for all-cause mortality in male patients with chronic renal disease on hemodialysis.

Multiple-breath washout to detect lung disease in patients with inborn errors of immunity.

Background: Pulmonary manifestations are the major cause of morbidity and mortality in patients with inborn errors of immunity (IEI). New and more sensitive diagnostic methods can potentially lead to earlier recognition and treatment of IEI lung disease and improve outcome. The aim of this study was to compare multiple-breath washout (MBW) and spirometry in patients with IEI and cystic fibrosis (CF) as well as healthy controls (HC) and to evaluate the sensitivity of lung clearance index (LCI) to assess lung disease in IEI. Methods: IEI patients (n=114) were recruited from our paediatric and adult immunodeficiency outpatient clinics and compared to age-matched CF patients (n=114) and HC (n=114). MBW measurements and spirometry were performed in the study participants, and MBW testing was repeated after 63-707 days in IEI patients (n=70). Results: The LCI was significantly higher in IEI patients than in HC (p<0.001) and significantly lower than in CF patients (p<0.001). The forced expiratory volume in 1 s (FEV1) z-score was significantly lower in IEI patients than in HC (p<0.01) and significantly higher than in CF patients (p<0.01). LCI and FEV1 z-score correlated moderately negatively in the total cohort, the IEI group and the CF group. Nineteen (20.7%) of 92 IEI patients and 35 (33.3%) of 105 CF patients had an elevated LCI but a normal FEV1 z-score. After a median of 364 days, the median LCI of 70 IEI patients increased significantly by 0.2. Conclusion: MBW is useful to detect lung disease in IEI and is more sensitive than spirometry.

Parental sex-dependent effects of either maternal or paternal eNOS deficiency on the offspring's phenotype without transmission of the parental eNOS deficiency to the offspring.

Background: Preclinical animal studies and clinical studies indicate that both maternal as well as paternal genetic alterations/gene defects might affect the phenotype of the next-generation without transmissions of the affected gene. Currently, the question of whether the same genetic defect present in the mother or father leads to a similar phenotype in the offspring remains insufficiently elucidated. Methods: In this head-to-head study, we crossbred female and male mice with heterozygous endothelial eNOS knockout (eNOS+/-) with male and female wild-type (wt) mice, respectively. Subsequently, we compared the phenotype of the resulting wt offspring with that of wt offspring born to parents with no eNOS deficiency. Results: Wt female offspring of mothers with heterozygous eNOS showed elevated liver fat accumulation, while wt male offspring of fathers with heterozygous eNOS exhibited increased fasting insulin, heightened insulin levels after a glucose load, and elevated liver glycogen content. By quantitative mass-spectrometry it was shown that concentrations of six serum metabolites (lysoPhosphatidylcholine acyl C20:3, phosphatidylcholine diacyl C36:2, phosphatidylcholine diacyl C38:1, phosphatidylcholine acyl-alkyl C34:1, phosphatidylcholine acyl-alkyl C36:3, and phosphatidylcholine acyl-alkyl C42:5 (PC ae C42:5) as well as four liver carbon metabolites (fructose 6-phosphate, fructose 1,6-bisphosphate, glucose 6-phosphate and fumarate) were different between wt offspring with eNOS+/- mothers and wt offspring with eNOS+/- fathers. Importantly, fumarate was inversely correlated with the liver fat accumulation in female offspring with eNOS+/- mothers and increased liver glycogen in offspring of both sexes with eNOS+/- fathers. The qRT-PCR results revealed that the gene expression patterns were different between wt offspring with eNOS+/- mothers and those offspring with eNOS+/- fathers. Different gene expression patterns were correlated with different observed phenotypic changes in male/female offspring born to mothers or fathers with a heterozygous eNOS genotype. Conclusion: The identical parental genetic alteration (heterozygous eNOS deficiency), without being passed on to the offspring, results in distinct metabolic, liver phenotype, and gene expression pattern variations depending on whether the genetic alteration originated from the father or the mother.