Early findings propose that impaired neurotransmission in the brain plays a key role in the pathophysiology of schizophrenia. Recent advances in understanding its multiple etiologies and pathogenetic mechanisms provide more speculative hypotheses focused on even broader somatic systems. Using a targeted tandem mass spectrometry (MS/MS)-based metabolomic platform, we compared metabolic signatures consisting of monoamine and amino acid neurotransmitter (NT) metabolites in plasma/urine simultaneously between first-episode neuroleptic-naïve schizophrenia patients (FENNS) and healthy controls before and after a 6-week risperidone monotherapy, which suggest that the patient NT profiles are restoring during treatment. To detect and identify potential biomarkers associated with schizophrenia and risperidone treatment, we also performed a combined ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) and 1H nuclear magnetic resonance (NMR)-based metabolomic profiling of the same samples, indicating a further deviation of the patients' global metabolic profile from that of controls. The NTs and their metabolites together with the 32 identified biomarkers underpin that metabolic pathways including NT metabolism, amino acid metabolism, glucose metabolism, lipid metabolism, energy metabolism, antioxidant defense system, bowel microflora and endocrine system are disturbed in FENNS. Among them, pregnanediol, citrate and α-ketoglutarate (α-KG) were significantly associated with symptomatology of schizophrenia after Bonferroni correction and may be useful biomarkers for monitoring therapeutic efficacy. These findings promise to yield valuable insights into the pathophysiology of schizophrenia and may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

Ferroptosis, a newly discovered iron-dependent cell death pathway, is characterized by lipid peroxidation and GSH depletion mediated by iron metabolism and is morphologically, biologically and genetically different from other programmed cell deaths. Besides, ferroptosis is usually found accompanied by inflammatory reactions. So far, it has been found participating in the development of many kinds of diseases. Macrophages are a group of immune cells that widely exist in our body for host defense and play an important role in tissue homeostasis by mediating inflammation and regulating iron, lipid and amino acid metabolisms through their unique functions like phagocytosis and efferocytosis, cytokines secretion and ROS production under different polarization. According to these common points in ferroptosis characteristics and macrophages functions, it’s obvious that there must be relationship between macrophages and ferroptosis. Therefore, our review aims at revealing the interaction between macrophages and ferroptosis concerning three metabolisms and integrating the application of certain relationship in curing diseases, mostly cancer. Finally, we also provide inspirations for further studies in therapy for some diseases by targeting certain resident macrophages in distinct tissues to regulate ferroptosis. Facts Ferroptosis is considered as a newly discovered form characterized by its nonapoptotic and iron-dependent lipid hydroperoxide, concerning iron, lipid and amino acid metabolisms. Ferroptosis has been widely found playing a crucial part in various diseases, including hepatic diseases, neurological diseases, cancer, etc. Macrophages are phagocytic immune cells, widely existing and owning various functions such as phagocytosis and efferocytosis, cytokines secretion and ROS production. Macrophages are proved to participate in mediating metabolisms and initiating immune reactions to maintain balance in our body. Recent studies try to treat cancer by altering macrophages’ polarization which damages tumor microenvironment and induces ferroptosis of cancer cells. Open questions How do macrophages regulate ferroptosis of other tissue cells specifically? Can we use the interaction between macrophages and ferroptosis in treating diseases other than cancer? What can we do to treat diseases related to ferroptosis by targeting macrophages? Is the use of the relationship between macrophages and ferroptosis more effective than other therapies when treating diseases?

Aims/hypothesisTo assess the effect of an angiotensin receptor blocker (ARB) on serum potassium and the effect of a serum potassium change on renal outcomes in patients with type 2 diabetes and nephropathy.MethodsWe performed a post hoc analysis in patients with type 2 diabetes participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Renal outcomes were defined as a composite of doubling of serum creatinine or end-stage renal disease.ResultsAt month 6, 259 (38.4%) and 73 (10.8%) patients in the losartan group and 151 (22.8%) and 34 (5.1%) patients in the placebo group had serum potassium ≥5.0 mmol/l and ≥5.5 mmol/l, (p < 0.001), respectively. Losartan was an independent predictor for serum potassium ≥5.0 mmol/l at month 6 (OR 2.8; 95% CI 2.0–3.9). Serum potassium at month 6 ≥ 5.0 mmol/l was in turn associated with increased risk for renal events (HR 1.22; 95% CI 1.00–1.50), independent of other risk factors. Adjustment of the overall treatment effects for serum potassium augmented losartan’s renoprotective effect from 21% (6–34%) to 35% (20–48%), suggesting that the renoprotective effects of losartan are offset by its effect on serum potassium.Conclusions/interpretationIn this study, we found that treatment with the ARB losartan is associated with a high risk of increased serum potassium levels, which is in turn associated with an increased risk of renal outcomes in patients with diabetes and nephropathy. Whether additional management of high serum potassium would further increase the renal protective properties of losartan is an important clinical question.

Background:Invasive fungal infection (IFI) is one of the leading causes of early death after renal transplantation. Voriconazole (VRC) is the first-line drug of IFI. Because of the large inter- and intraindividual variability in VRC plasma concentrations and the narrow therapeutic window for treating patients with IFIs, it is crucial to study the factors which could influence pharmacokinetic variability. We performed a population pharmacokinetics (PPK) study of VRC for personalized medicine.Methods:A total of 125 trough concentrations (Cmin) from 56 patients were evaluated, retrospectively. Nonlinear mixed effect model was used to describe a PPK model that was internally validated by bootstrap method. Potential covariates included demographic characteristics, physiological and pathological data, concomitant medications, and CYP2C19 genotype.Results:A 1-compartment model with first-order absorption and elimination was fit to characterize the VRC pharmacokinetics in renal transplant recipients (RTRs). Aspartate aminotransferase (AST) had a significant influence on clearance (CL) while CYP2C19 genotype had a major impact on the volume of distribution (V). The parameters of CL and V were 4.76 L/h and 22.47 L, respectively. The final model was V (L) = 22.47 × [1 + 2.21 × (EM = 1)] × [1 + 4.67 × (IM = 1)] × [1 + 3.30 × (PM = 1)] × exp (0.96); CL (L/h) = 4.76 × (AST/33)^(−0.23) × exp (0.14). VRC Cmin in intermediate metabolizers was significantly higher than in extensive metabolizers.Conclusions:Liver function and CYP2C19 polymorphism are major determinants of VRC pharmacokinetic variability in RTRs. Genotypes and clinical biomarkers can determine the initial scheme. Subsequently, therapeutic drug monitoring can optimize clinical efficacy and minimize toxicity. Hence, this is a feasible way to facilitate personalized medicine in RTRs. In addition, it is the first report about PPK of VRC in RTRs.