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In 2030, the World Health Organization estimates that more than 350 million people will be diagnosed with diabetes. Consequently, Metformin - the biguanide drug of choice orally administered for diabetes type II - is anticipated to see a spike in production. Unlike many pharmaceutical drugs, Metformin (Met) is not metabolized by humans but passes through the body unchanged. Entering aquatic compartments, such as in sewage, it can be bacterially transformed to the ultimate transformation product Guanylurea (Gua). Sampling over one week (n=5) from a Southern German sewage treatment plant revealed very high average (AV) concentrations in influent (AVMet=111,800ng/L, AVGua=1300ng/L) and effluent samples (AVMet=4800ng/L, AVGua=44,000ng/L). To provide a more complete picture of the distribution and potential persistence of these compounds in the German water cycle, a new, efficient and highly sensitive liquid chromatography mass spectrometric method with direct injection was used for the measurement of Metformin and Guanylurea in drinking, surface, sewage and seawater. Limits of quantification (LOQ) ranging from 2-10ng/L allowed the detection of Metformin and Guanylurea in different locations such as: Lake Constance (n=11: AVMet=102ng/L, AVGua=16ng/L), river Elbe (n=12: AVMet=472ng/L, AVGua=9ng/L), river Weser (n=6: AVMet=349ng/L, AVGua=137ng/L) and for the first time in marine North Sea water (n=14: AVMet=13ng/L, AVGua=11ng/L). Based on daily water discharges, Metformin loads of 15.2kg/d (Elbe) and 6.4kg/d (Weser) into the North Sea were calculated. Lake Constance is used to abstract potable water which is further purified to be used as drinking water. A first screening of two tap water samples contained 2ng/L and 61ng/L of Metformin, respectively. The results of this study suggest that Metformin and Guanylurea could be distributed over a large fraction of the world's potable water sources and oceans. With no natural degradation processes, these compounds can be easily reintroduced to humans as they enter the food chain.

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Summary PINK1 loss-of-function mutations cause early onset Parkinson disease. PINK1-Parkin mediated mitophagy has been well studied, but the relevance of the endogenous process in the brain is debated. Here, the absence of PINK1 in human dopaminergic neurons inhibits ionophore-induced mitophagy and reduces mitochondrial membrane potential. Compensatory, mitochondrial renewal maintains mitochondrial morphology and protects the respiratory chain. This is paralleled by metabolic changes, including inhibition of the TCA cycle enzyme m Aconitase, accumulation of NAD + , and metabolite depletion. Loss of PINK1 disrupts dopamine metabolism by critically affecting its synthesis and uptake. The mechanism involves steering of key amino acids toward energy production rather than neurotransmitter metabolism and involves cofactors related to the vitamin B6 salvage pathway identified using unbiased multi-omics approaches. We propose that reduction of mitochondrial membrane potential that cannot be controlled by PINK1 signaling initiates metabolic compensation that has neurometabolic consequences relevant to Parkinson disease.

The proper communication between gut and brain is pivotal for the maintenance of health and, dysregulation of the gut-brain axis can lead to several clinical disorders. In Parkinson’s disease (PD) 85% of all patients experienced constipation many years before showing any signs of motor phenotypes. For differential diagnosis and preventive treatment, there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperone protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 influences the risk of PD remains incompletely understood. In the present study, we provide evidence that DJ-1 is implicated in shaping the gut microbiome including; their metabolite production, inflammation and innate immune cells (ILCs) development. We revealed that deficiency of DJ-1 leads to a significant increase in two specific genera/species, namely Alistipes and Rikenella. In DJ-1 knock-out (DJ-1-/-) mice the production of fecal calprotectin and MCP-1 inflammatory proteins were elevated. Fecal and serum metabolic profile showed that malonate which influences the immune system was significantly more abundant in DJ-1−/− mice. DJ-1 appeared also to be involved in ILCs development. Further, inflammatory genes related to PD were augmented in the midbrain of DJ-1−/− mice. Our data suggest that metabolites and inflammation produced in the gut could be used as biomarkers for PD detection. Perhaps, these metabolites and inflammatory mediators could be involved in triggering inflammation resulting in PD pathology.

Rationale: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important regulators of inflammation. The exact impact of ROS/RNS on cutaneous delayed-type hypersensitivity reaction (DTHR) is controversial. The aim of our study was to identify the dominant sources of ROS/RNS during acute and chronic trinitrochlorobenzene (TNCB)-induced cutaneous DTHR in mice with differently impaired ROS/RNS production. Methods: TNCB-sensitized wild-type, NADPH oxidase 2 (NOX2)- deficient (gp91 phox-/- ), myeloperoxidase-deficient (MPO -/- ), and inducible nitric oxide synthase-deficient (iNOS -/- ) mice were challenged with TNCB on the right ear once to elicit acute DTHR and repetitively up to five times to induce chronic DTHR. We measured ear swelling responses and noninvasively assessed ROS/RNS production in vivo by employing the chemiluminescence optical imaging (OI) probe L-012. Additionally, we conducted extensive ex vivo analyses of inflamed ears focusing on ROS/RNS production and the biochemical and morphological consequences. Results: The in vivo L-012 OI of acute and chronic DTHR revealed completely abrogated ROS/RNS production in the ears of gp91 phox-/- mice, up to 90 % decreased ROS/RNS production in the ears of MPO -/- mice and unaffected ROS/RNS production in the ears of iNOS -/- mice. The DHR flow cytometry analysis of leukocytes derived from the ears with acute DTHR confirmed our in vivo L-012 OI results. Nevertheless, we observed no significant differences in the ear swelling responses among all the experimental groups. The histopathological analysis of the ears of gp91 phox-/- mice with acute DTHRs revealed slightly enhanced inflammation. In contrast, we observed a moderately reduced inflammatory immune response in the ears of gp91 phox-/- mice with chronic DTHR, while the inflamed ears of MPO -/- mice exhibited the strongest inflammation. Analyses of lipid peroxidation, 8-hydroxy-2'deoxyguanosine levels, redox related metabolites and genomic expression of antioxidant proteins revealed similar oxidative stress in all experimental groups. Furthermore, inflamed ears of wild-type and gp91 phox-/- mice displayed neutrophil extracellular trap (NET) formation exclusively in acute but not chronic DTHR. Conclusions: MPO and NOX2 are the dominant sources of ROS/RNS in acute and chronic DTHR. Nevertheless, depletion of one primary source of ROS/RNS exhibited only marginal but conflicting impact on acute and chronic cutaneous DTHR. Thus, ROS/RNS are not a single entity, and each species has different properties at certain stages of the disease, resulting in different outcomes.

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