Proteomic and metabolomic profiling reveals time-dependent changes in hippocampal metabolism upon paroxetine treatment and biomarker candidates

Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of monoamine reuptake inhibition are poorly understood and yet presumably important for the drugs' mode of action. In the present study we aimed at identifying hippocampal cellular pathway alterations in DBA/2 mice using paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Furthermore we identified biomarker candidates for the assessment of antidepressant treatment effects in plasma. Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo¹⁵N metabolic labeling combined with mass spectrometry. We also studied the time course of metabolite level changes in hippocampus and plasma using a targeted polar metabolomics profiling platform. In silico pathway analyses revealed profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. In the course of our analyses we also identified myo-inositol as a biomarker candidate for the assessment of antidepressant treatment effects in the periphery. This study defines the cellular response to paroxetine treatment at the proteome and metabolome levels in the hippocampus of DBA/2 mice and suggests novel SSRI modes of action that warrant consideration in antidepressant development efforts.     

The association of endothelial cell signaling,severity of illness,and organ dysfunction in sepsis

Introduction  

Previous reports suggest that endothelial activation is an important process in sepsis pathogenesis. We investigated the association between biomarkers of endothelial cell activation and sepsis severity, organ dysfunction sequential organ failure assessment (SOFA) score, and death.     

Serum and Urine Metabolites in Healthy Men after Consumption of Acidified Milk and Yogurt

The identification of molecular biomarkers that can be used to quantitatively link dietary intake to phenotypic traits in humans is a key theme in modern nutritional research. Although dairy products (with and without fermentation) represent a major food group, the identification of markers of their intake lags behind that of other food groups. Here, we report the results from an analysis of the metabolites in postprandial serum and urine samples from a randomized crossover study with 14 healthy men who ingested acidified milk, yogurt, and a non-dairy meal. Our study confirms the potential of lactose and its metabolites as markers of lactose-containing dairy foods and the dependence of their combined profiles on the fermentation status of the consumed products. Furthermore, indole-3-lactic acid and 3-phenyllactic acid are two products of fermentation whose postprandial behaviour strongly discriminates yogurt from milk intake. Our study also provides evidence of the ability of milk fermentation to increase the acute delivery of free amino acids to humans. Notably, 3,5-dimethyloctan-2-one also proves to be a specific marker for milk and yogurt consumption, as well as for cheese consumption (previously published data). These molecules deserve future characterisation in human interventional and observational studies.     

Subgroups in the treatment of nasal polyposis with dupilumab: A retrospective study

Dupilumab has been shown to be safe and effective in treating chronic rhinosinusitis with polyposis (CRSwNP). There is to this date no published data whether subgroups like patients with aspirin exacerbated respiratory disease (AERD), increased histologic eosinophilia or elevated blood eosinophil or IgE-levels benefit greater from dupilumab therapy. Moreover, there is no data comparing the efficacy of functional endoscopic sinus surgery (FESS) with dupilumab therapy. We conducted a retrospective chart review of all patients that were treated at a tertiary referral center for CRswNP with dupilumab. We also contacted the patients with a questionnaire to evaluate the efficacy of previous surgeries and dupilumab therapy by visual analogue scale (VAS) and the glasgow benefit inventory (GBI) as well as report on side effects. Overall, 75 patients were included in the study at hand that reported back 138 times. While dupilumab treatment was efficient, we found no systematic evidence of greater efficacy of dupilumab in patients with AERD, histologic eosinophilia or increased blood eosinophil or IgE-levels. All patients showed a considerable decrease in subjective burden of disease, objective smell tests and endoscopic findings. From the patients point of view, dupilumab therapy showed greater efficacy both in the VAS and the GBI overall and all subcategories but “social support.” Dupilumab is efficient in treating CRSwNP; this effect is independent from disease characteristics like AERD, histologic eosinophilia, serum IgE-levels or eosinophil counts. There seems to be a group of patients that benefit greater from dupilumab therapy compared to FESS.     

Risk factors for internalizing symptoms: The influence of empathy,theory of mind,and negative thinking processes

Internalizing symptoms such as elevated stress and sustained negative affect can be important warning signs for developing mental disorders. A recent theoretical framework suggests a complex interplay of empathy, theory of mind (ToM), and negative thinking processes as a crucial risk combination for internalizing symptoms. To disentangle these relationships, this study utilizes neural, behavioral, and self-report data to examine how the interplay between empathy, ToM, and negative thinking processes relates to stress and negative affect. We reanalyzed the baseline data of N = 302 healthy participants (57% female, M_age = 40.52, SD_age = 9.30) who participated in a large-scale mental training study, the ReSource project. Empathy and ToM were assessed using a validated fMRI paradigm featuring naturalistic video stimuli and via self-report. Additional self-report scales were employed to measure internalizing symptoms (perceived stress, negative affect) and negative thinking processes (rumination and self-blame). Our results revealed linear associations of self-reported ToM and empathic distress with stress and negative affect. Also, both lower and higher, compared to average, activation in the anterior insula during empathic processing and in the middle temporal gyrus during ToM performance was significantly associated with internalizing symptoms. These associations were dependent on rumination and self-blame. Our findings indicate specific risk constellations for internalizing symptoms. Especially people with lower self-reported ToM and higher empathic distress may be at risk for more internalizing symptoms. Quadratic associations of empathy- and ToM-related brain activation with internalizing symptoms depended on negative thinking processes, suggesting differential effects of cognitive and affective functioning on internalizing symptoms. Using a multi-method approach, these findings advance current research by shedding light on which complex risk combinations of cognitive and affective functioning are relevant for internalizing symptoms.