Succinate dehydrogenase complex II inhibitors (SDHIs) are widely used fungicides since the 1960s. Recently, based on published in vitro cell viability data, potential health effects via disruption of the mitochondrial respiratory chain and tricarboxylic acid cycle have been postulated in mammalian species. As primary metabolic impact of SDH inhibition, an increase in succinate, and compensatory ATP production via glycolysis resulting in excess lactate levels was hypothesized. To investigate these hypotheses, genome-scale metabolic models of Rattus norvegicus and Homo sapiens were used for an in silico analysis of mammalian metabolism. Moreover, plasma samples from 28-day studies with the SDHIs boscalid and fluxapyroxad were subjected to metabolome analyses, to assess in vivo metabolite changes induced by SDHIs. The outcome of in silico analyses indicated that mammalian metabolic networks are robust and able to compensate different types of metabolic perturbation, e.g., partial or complete SDH inhibition. Additionally, the in silico comparison of rat and human responses suggested no noticeable differences between both species, evidencing that the rat is an appropriate testing organism for toxicity of SDHIs. Since no succinate or lactate accumulation were found in rats, such an accumulation is also not expected in humans as a result of SDHI exposure.The citrus plants of the Rutaceae, such as oranges, grapefruits and mandarins, are cultivated worldwide. Their fruits and their juices are rich sources of flavonoids for example, hesperidin and narirutin in oranges, and narirutin and naringin in grapefruits. Although these flavonoids have been found to potentially modulate blood platelet activity, most studies have been performed in vitro; in addition, the body of evidence regarding antiplatelet activity is relatively weak and the exact mechanisms remain poorly understood. More importantly, the concentrations of flavonoids studied in vitro (i.e. 3.125-300 μM) with washed blood platelets did not always correspond with their physiological concentrations in vivo, i.e. in whole blood after oral administration, and citrus fruit flavonoids are also characterized by low bioavailability. Therefore, more detailed studies on the antiplatelet potential of citrus flavonoids are needed, especially in in vivo models.Monoamine oxidase (MAO) enzymes, type A and B metabolise the amine neurotransmitters of the body. LXS196 Selective inhibition of either enzyme is an approach for treating neurodegenerative and stress-induced disorders, and inhibition of an enzyme is proportional to the binding of the MAO inhibitor. Conventionally, the binding of test compounds to enzymes is assessed by radiolabelled ligands in ex vivo and in vivo occupancy assays. Regulatory restrictions and turnaround time are the limitations of the methods that use radiolabelled ligands. But the use of non-radiolabelled tracers and sensitive mass spectrometry (LC-MS/MS) based assays accelerated the determination of target occupancy in pre-clinical species. A report on use of non-radiolabelled ligand in in vivo MAO occupancy assay is not available. The objectives of the present study were to optimise non-radiolabelled harmine and deprenyl as selective tracers in MAO-A and MAO-B occupancy assays and evaluate MAO occupancy of test compounds in rat brain. Tracer optimitable pre-clinical tools to determine MAO occupancy. To (1) examine the contemporary incidence of occult inguinal LN metastases and (2) identify predictors of occult inguinal LN metastases to improve selection of cN0 patients for inguinal lymphadenectomy (ILND). We identified 590 men with cTany cN0 cM0 penile cancer who underwent partial/radical penectomy and ILND from 2006-2016 in the NCDB. Rates of pN+ disease were examined, and a multivariable regression model was constructed to identify features associated with pN+ disease. Tumors were ≤pT1 in 21%, pT2 in 43%, and pT3/pT4 in 24% of patients. A median of 15 (IQR 8-22) LNs were removed at ILND. The overall pN+ rate was 24% and did not vary over the study period. The pN+ rate, stratified by pT stage, varied from 18-33%. On multivariable analysis, only higher tumor grade (OR 2.16; P=0.02 for grade 2; OR 2.81; P=0.005 for grade 3-4, versus grade 1) and lymphovascular invasion (OR 3.12; P <0.001) were independently associated with pN+ disease, whereas pT stage was not. The contemporary rate of occult LN metastases in men with cN0 penile cancer remains high at approximately 24%. Our results suggest that high tumor grade and/or lymphovascular invasion are better determinants of lymph node involvement than primary tumor stage.The contemporary rate of occult LN metastases in men with cN0 penile cancer remains high at approximately 24%. Our results suggest that high tumor grade and/or lymphovascular invasion are better determinants of lymph node involvement than primary tumor stage.Diabetic retinopathy (DR), the most common ocular complication resulting from diabetes in working-age adults, causes vision impairment and even blindness because of microvascular damage to the retina. Melatonin is an endogenous neurohormone possessing various biological properties, including the regulation of oxidative stress, inflammation, autophagy, and angiogenesis functions. To evaluate the effects of melatonin on DR, we first investigated the role of melatonin in retinal angiogenesis and inner blood-retina barrier (iBRB) under high glucose conditions in vitro and in vivo. Melatonin administration ameliorated high glucose-induced iBRB disruption, cell proliferation, cell migration, invasion and tube formation, and decreased the expression levels of VEGF, MMP-2, and MMP-9. Furthermore, melatonin treatment increased the level of autophagy but decreased the expression levels of inflammation-related factors under high glucose conditions. To further explore the underlying mechanism, we evaluated human retinal microvascular endothelial cells (HRMECs) via tandem mass tags (TMT)-labeled quantitative proteomics under high-glucose conditions with or without melatonin. Bioinformatics analysis results revealed that the main enrichment pathway of differentially expressed proteins (DEPs) was the Wnt pathway. We found that melatonin inhibited the activation of Wnt/β-catenin pathway following DR. These abovementioned protective effects of melatonin under hyperglycemia were blocked by lithium chloride (LiCl; activator of the Wnt/β-catenin signaling pathway). In summary, melatonin exerts protective effects on experimental DR via inhibiting Wnt/β-catenin pathway by, at least partially, alleviating autophagic dysfunction and inflammatory activation.