Metabolomic signatures associated with depression and predictors of antidepressant response in humans: A CAN-BIND-1 report.

One of the biggest challenges in treating depression is the heterogeneous and qualitative nature of its clinical presentations. This highlights the need to find quantitative molecular markers to tailor existing treatment strategies to the individual's biological system. In this study, high-resolution metabolic phenotyping of urine and plasma samples from the CAN-BIND study collected before treatment with two common pharmacological strategies, escitalopram and aripiprazole, was performed. Here we show that a panel of LDL and HDL subfractions were negatively correlated with depression in males. For treatment response, lower baseline concentrations of apolipoprotein A1 and HDL were predictive of escitalopram response in males, while higher baseline concentrations of apolipoprotein A2, HDL and VLDL subfractions were predictive of aripiprazole response in females. These findings support the potential of metabolomics in precision medicine and the possibility of identifying personalized interventions for depression.

Relationship of methylglyoxal-adduct biogenesis to LDL and triglyceride levels in diabetics.

AIMS: Protein glycation leading to advanced glycation-endproducts (AGE) is enhanced in diabetes by increased blood glucose and collateral endogenous production of reactive α-dicarbonyls. Among AGE precursors, methylglyoxal (MG) is considered as one of the key intermediates. We hypothesized it to be a common product of both carbonyl and oxidative stress, and investigated its biogenesis in relation to glycemic and lipid status in diabetic patients. METHODS: Serum and urine MG-adducts were measured by competitive immunofluorometric assay in 83 diabetic and 20 healthy subjects. KEY FINDINGS: A significant association of MG-adducts serum level with LDL (r=0.31;p=0.003) was observed. A correlation between LDL-c, HDL-C and PPG as independent variables and serum MG-adducts as a dependent variable was found (p<0.014) using multiple stepwise regression, whereas urine albumin/creatinine ratio was independently associated with urine MG-adducts. LDL cut-off >3.0mmol/l discriminated patients with higher serum MG-adducts (p=0.0052), although there was no between-subgroup difference in glycemic control. Patients on statin therapy had a lower MG-adduct level. The positive relationship between LDL-c and MG-adducts (r=0.38;p=0.042) was noted in patients free of statin treatment, whereas an inverse tendency was found in the statin-treated subgroup. SIGNIFICANCE: Significant relationship between LDL and MG-adduct production, as well as tight correlation between triglycerides and urinary MG-adduct excretion suggest that the lipoxidation and glyceraldehyde-3-phosphate route, along with the glycolytic pathway, might be an important source of MG generation. The glycotoxin methylglyoxal seems to be a common factor linking hyperglycemia and intensive lipolysis, two dominant metabolic changes in diabetes.

Evaluation of biomarkers of exposure and potential harm in smokers, former smokers and never-smokers.

BACKGROUND: The objective of this study was to obtain baseline data on biomarkers of exposure (BoE) and biomarkers of potential harm (BoPH) in smokers, former smokers and never-smokers. METHODS: This was a cross-sectional study of 80 healthy male and female volunteers over 21 years old, self-selected for smoking status. Subjects were prescreened by medical staff at an independent clinical research unit, within 1 week prior to a single overnight residential visit and sample collection. RESULTS: All BoE were able to differentiate between the two smoking groups and smokers from all nonsmokers. There was a strong correlation between cigarettes smoked per day and total urinary nicotine equivalents (TNE; r=0.85). TNE correlated better with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels than cigarettes smoked per day (r=0.75 and r=0.56, respectively). Of the BoPH included in this study, seven (11-dehydro-thromboxane B2, 2, 3-dinorthrom-boxane B2, 8-epi prostaglandin F(2alpha), 8-hydroxy-2 deoxyguanosine, cis-thymidine glycol, low-density lipoprotein cholesterol and IgG) were significantly different between the group who smoked more cigarettes per day and never-smokers. These differences became more apparent and extended to the group who smoked 10 or less cigarettes per day, when total urinary recovery values were corrected for creatinine clearance. CONCLUSIONS: While BoE clearly differentiate between groups based on self-declared smoking status, most BoPH examined could not do so in a consistent manner. The dynamics of BoPH levels are not well understood. Future studies of BoPH should eliminate potential confounding factors and increase the number of subjects to allow the investigation of genetic polymorphism in metabolic pathways.

Growth hormone induces low-density lipoprotein clearance but not bile acid synthesis in humans.

OBJECTIVE: Growth hormone (GH) induces hepatic low-density lipoprotein (LDL) receptors and lowers plasma cholesterol. We characterized the influence of GH treatment on plasma LDL clearance in normal humans and investigated the relative role of LDL receptor (LDLR) activity and stimulation of bile acid synthesis in subjects with different LDLR expression. METHODS AND RESULTS: Plasma clearance of autologous 125I-LDL was measured before and during 3 weeks of treatment with GH (0.1 IU/kg per day) in 9 healthy young males. Plasma LDL cholesterol was reduced by 13% and the fractional catabolic rate of LDL increased by 27%. More marked changes were seen in a patient with hypopituitarism substituted with GH (0.07 IU/kg per day) for 3 months. In a second study, GH dose-dependently reduced LDL cholesterol and increased Lp(a) levels in 3 groups of males: younger and elderly healthy subjects and heterozygous familial hypercholesterolemia (FH). No effect on bile acid synthesis measured by the plasma marker 7alpha-hydroxy-4-cholesten-3-one was observed. In an LDLR-deficient FH homozygote, LDL cholesterol was not affected by GH. CONCLUSIONS: GH treatment reduces plasma LDL cholesterol by inducing LDL clearance. In humans, LDLR expression is a prerequisite for this effect, whereas it is not related to stimulation of bile acid synthesis.

Short-term effects of fish oil treatment on urinary excretion of high- and low-molecular weight proteins in patients with IgA nephropathy.

AIMS: Recently, it was shown that fish oil treatment improved renal survival in patients with IgA nephropathy. The precise mechanisms of this protective effect remained unclear. Omega-3 polyunsaturated fatty acids (PUFAs), important active substances of fish oil, are able to attenuate inflammatory responses. Thus, the renoprotective effects of fish oil may be the result of mitigation of glomerular or tubulo-interstitial inflammation. We hypothesized that such a decrease in glomerular or tubulo-interstitial inflammation could result in an improvement of glomerular permselectivity as reflected by the urinary excretion of IgG, or of tubular reabsorption capacity as reflected by the urinary excretion of low-molecular weight proteins (LMWPs), or a decrease of the excretion of the inflammatory mediators MCP-1 and TNF-alpha. METHODS: Twelve patients with a biopsy-proven IgA nephropathy, a persistent proteinuria of > 0.5 g/24 h, and an impairment of renal function (creatinine clearance 44 ml/min/1.73 m2, range 19-72) were treated with fish oil for 6 months. The daily dosage of PUFAs amounted to 3.0 g. Before start of treatment (month 0), at the end of treatment (month 6), and 6 months off treatment (month 12), renal measurements were carried out. Creatinine clearance (ECC) was measured after pretreatment with cimetidine. In timed urine samples albumin, IgG, the LMWPs beta2-microglobulin and alpha1-microglobulin, and both MCP-1 and TNF-alpha were measured. RESULTS: Six months of fish oil treatment had no effect on creatinine clearance (44 ml/min/1.73 m2 vs 42 ml/min/1.73 m2), the urinary excretion of albumin (1,594 +/- 284 vs 1,370 +/- 337 microg/min), IgG (84 +/- 16 vs 82 +/- 20 microg/min), beta2-microglobulin (medians: 1.0 vs 0.8 microg/min), alpha1-microglobulin (38 +/- 9 vs 53 +/- 15 microg/min), MCP-1 (medians: 720 vs 782 microg/min), or TNF-alpha (medians: 31 vs 27 microg/min). Mean arterial pressure gradually decreased from 102 +/- 4 to 96 +/- 4 mmHg at the end of the treatment (n.s.), however, the lowest value was observed after fish oil had been stopped for 6 months (93 +/- 3 mmHg, p < 0.05). Changes in the excretion of the urinary proteins during the 12-month study period were correlated to changes in blood pressure (r = 0.57, p < 0.01), independent of fish oil treatment. The course of the disease over the 12-month study period in our fish oil-treated patients was comparable to that of an untreated control group. CONCLUSIONS: Fish oil treatment in patients with IgA nephropathy, renal insufficiency and proteinuria did not affect the excretion of low- or high-molecular weight proteins, MCP-1 or TNF-alpha. Our data do not provide arguments for beneficial effects of fish oil treatment on glomerular permselectivity of tubulo-interstitial inflammation.