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Selenophenoquinolinone is a prospective scaffold for the development of ABCB1 inhibitors for the treatment of MDR cancers.

Significant impairments in mitochondrial function are associated with the development of multi-organ failure in sepsis/endotoxaemia, but the data on the dynamics of simultaneous mitochondrial impairment in multiple organs are limited. The aim of this study was to evaluate the changes in heart, brain and kidney mitochondrial function in an experimental model of lipopolysaccharide (LPS)-induced endotoxaemia.Samples were collected 4 and 24 h after single injection of LPS (10 mg/kg) in mice. Marked increases in inflammation-related gene expression were observed in all studied tissues 4 h after LPS administration. At 24 h post LPS administration, this expression of inflammation-related genes remained upregulated only in kidneys. Significantly increased concentrations of kidney function markers confirmed that kidneys were severely damaged. Echocardiographic measurements showed that the ejection fraction and fractional shortening were significantly reduced 4 h after LPS administration, whereas 24 h after LPS administration, the cardiac function was restored to baseline. A two-fold decrease in mitochondrial oxidative phosphorylation (OXPHOS) capacity in the kidney was observed 4 and 24 h after LPS administration. Significant decrease in mitochondrial fatty acid oxidation was observed in heart 4 h after LPS administration. Furthermore, 24 h after LPS administration, the respiration rates in cardiac fibers at OXPHOS and electron transport (ET) states were significantly increased, which resulted in increased ET coupling efficiency in the LPS-treated group, whereas four-fold increases in the H2O2 production rate and H2O2/O ratio were observed. The brain mitochondria demonstrated a slightly impaired mitochondrial functionality just 24 h after the induction of endotoxaemia.In conclusion, among studied tissues kidney mitochondria are the most sensitive to endotoxaemia and do not recover from LPS-induced damage, whereas in brain, mitochondrial function was not significantly altered. In heart, endotoxaemia induces a decrease in the mitochondrial fatty acid oxidation capacity, but during the phase of suppressed inflammatory response, the ET efficiency is improved despite the marked increase in reactive oxygen species production.

Increased tissue content of long-chain acylcarnitines may induce mitochondrial and cardiac damage by stimulating ROS production. N6-trimethyllysine dioxygenase (TMLD) is the first enzyme in the carnitine/acylcarnitine biosynthesis pathway. Inactivation of the TMLHE gene (TMLHE KO) in mice is expected to limit long-chain acylcarnitine synthesis and thus induce a cardio- and mitochondria-protective phenotype. TMLHE gene deletion in male mice lowered acylcarnitine concentrations in blood and cardiac tissues by up to 85% and decreased fatty acid oxidation by 30% but did not affect muscle and heart function in mice. Metabolome profile analysis revealed increased levels of polyunsaturated fatty acids (PUFAs) and a global shift in fatty acid content from saturated to unsaturated lipids. In the risk area of ischemic hearts in TMLHE KO mouse, the OXPHOS-dependent respiration rate and OXPHOS coupling efficiency were fully preserved. Additionally, the decreased long-chain acylcarnitine synthesis rate in TMLHE KO mice prevented ischaemia-reperfusion-induced ROS production in cardiac mitochondria. This was associated with a 39% smaller infarct size in the TMLHE KO mice. The arrest of the acylcarnitine biosynthesis pathway in TMLHE KO mice prevents ischaemia-reperfusion-induced damage in cardiac mitochondria and decreases infarct size. These results confirm that the decreased accumulation of ROS-increasing fatty acid metabolism intermediates prevents mitochondrial and cardiac damage during ischaemia-reperfusion.

Long-chainω-3 polyunsaturated fatty acids (PUFAs) are known to induce cardiometabolic benefits, but the metabolic pathways of their biosynthesis ensuring sufficient bioavailability require further investigation. Here, we show that a pharmacological decrease in overall fatty acid utilization promotes an increase in the levels of PUFAs and attenuates cardiometabolic disturbances in a Zucker rat metabolic syndrome model. Metabolome analysis showed that inhibition of fatty acid utilization by methyl-GBB increased the concentration of PUFAs but not the total fatty acid levels in plasma. Insulin sensitivity was improved, and the plasma insulin concentration was decreased. Overall, pharmacological modulation of fatty acid handling preserved cardiac glucose and pyruvate oxidation, protected mitochondrial functionality by decreasing long-chain acylcarnitine levels, and decreased myocardial infarct size twofold. Our work shows that partial pharmacological inhibition of fatty acid oxidation is a novel approach to selectively increase the levels of PUFAs and modulate lipid handling to prevent cardiometabolic disturbances.

The current study aimed to explore whether metformin, the most widely prescribed oral medication for the treatment of type 2 diabetes, alters plasma levels of cardiometabolic disease-related metabolite trimethylamine N-oxide (TMAO) in db/db mice with type 2 diabetes. TMAO plasma concentration was up to 13.2-fold higher in db/db mice when compared to control mice, while in db/db mice fed choline-enriched diet, that mimics meat and dairy product intake, TMAO plasma level was increased 16.8-times. Metformin (250 mg/kg/day) significantly decreased TMAO concentration by up to twofold in both standard and choline-supplemented diet-fed db/db mice plasma. In vitro, metformin significantly decreased the bacterial production rate of trimethylamine (TMA), the precursor of TMAO, from choline up to 3.25-fold in K. pneumoniae and up to 26-fold in P. Mirabilis, while significantly slowing the growth of P. Mirabilis only. Metformin did not affect the expression of genes encoding subunits of bacterial choline-TMA-lyase microcompartment, the activity of the enzyme itself and choline uptake, suggesting that more complex regulation beyond the choline-TMA-lyase is present. To conclude, the TMAO decreasing effect of metformin could be an additional mechanism behind the clinically observed cardiovascular benefits of the drug.

Acylcarnitine accumulation has been linked to perturbations in energy metabolism pathways. In this study, we demonstrate that long-chain (LC) acylcarnitines are active metabolites involved in the regulation of glucose metabolism in vivo. Single-dose administration of palmitoylcarnitine (PC) in fed mice induced marked insulin insensitivity, decreased glucose uptake in muscles, and elevated blood glucose levels. Increase in the content of LC acylcarnitine induced insulin resistance by impairing Akt phosphorylation at Ser473. The long-term administration of PC using slow-release osmotic minipumps induced marked hyperinsulinemia, insulin resistance, and glucose intolerance, suggesting that the permanent accumulation of LC acylcarnitines can accelerate the progression of insulin resistance. The decrease of acylcarnitine content significantly improved glucose tolerance in a mouse model of diet-induced glucose intolerance. In conclusion, we show that the physiological increase in content of acylcarnitines ensures the transition from a fed to fasted state in order to limit glucose metabolism in the fasted state. In the fed state, the inability of insulin to inhibit LC acylcarnitine production induces disturbances in glucose uptake and metabolism. The reduction of acylcarnitine content could be an effective strategy to improve insulin sensitivity. © 2017 BioFactors, 43(5):718-730, 2017.

There is a growing body of evidence demonstrating the significant involvement of the sigma-1 chaperone protein in the modulation of seizures. Several sigma-1 receptor (Sig1R) ligands have been demonstrated to regulate the seizure threshold in acute and chronic seizure models. However, the mechanism by which Sig1R modulates the excitatory and inhibitory pathways in the brain has not been elucidated. The aim of this study was to compare the susceptibility to seizures of wild type (WT) and Sig1R knockout (Sig1R−/−) mice in intravenous pentylenetetrazol (PTZ) and (+)-bicuculline (BIC) infusion-induced acute seizure and Sig1R antagonist NE-100-induced seizure models. To determine possible molecular mechanisms, we used quantitative PCR, Western blotting and immunohistochemistry to assess the possible involvement of several seizure-related genes and proteins. Peripheral tissue contractile response of WT and Sig1R−/− mice was studied in an isolated vasa deferentia model. The most important finding was the significantly decreased expression of the R2 subunit of the GABA-B receptor in the hippocampus and habenula of Sig1R−/− mice. Our results demonstrated that Sig1R−/− mice have decreased thresholds for PTZ- and BIC-induced tonic seizures. In the NE-100-induced seizure model, Sig1R−/− animals demonstrated lower seizure scores, shorter durations and increased latency times of seizures compared to WT mice. Sig1R-independent activities of NE-100 included downregulation of the gene expression of iNOS and GABA-A γ2 and inhibition of KCl-induced depolarization in both WT and Sig1R−/− animals. In conclusion, the results of this study indicate that the lack of Sig1R resulted in decreased expression of the R2 subunit of the GABA-B receptor and increased susceptibility to seizures. Our results confirm that Sig1R is a significant molecular target for seizure modulation and warrants further investigation for the development of novel anti-seizure drugs.

Babesia spp. are tick-borne protozoan parasites that have been reported in many European countries and are considered to be emerging pathogens. Several Babesia spp. have been identified in ticks in Latvia. Recently, canine babesiosis cases were diagnosed for the first time in Latvia; therefore, continued studies on the prevalence and occurrence of new species are warranted. In the present study, questing tick samples collected in 2005-2007 were screened for the presence of Babesia spp.; in total, 432 Ixodes ricinus and 693 Ixodes persulcatus ticks were analyzed. Babesia spp. were detected in 1.4% of the I. ricinus ticks and in 1.9% of I. persulcatus ticks. Sequencing revealed that ixodid ticks in Latvia contained Babesia microti, Babesia capreoli, and Babesia venatorum. Babesia microti was the most prevalent species, accounting for 58% of all positive samples; moreover, two distinct B. microti genotypes were identified. Phylogenetic analysis of the full-length 18S rRNA gene of two B. capreoli/B. divergens isolates indicated a closer relationship to the B. capreoli clade than B. divergens. This is the first report of B. venatorum in I. persulcatus ticks in Latvia. Our results suggest that both I. ricinus and I. persulcatus ticks play important roles in the epidemiology of these zoonotic pathogens in Latvia.

Acylcarnitine accumulation has been linked to perturbations in energy metabolism pathways. In this study, we demonstrate that long-chain (LC) acylcarnitines are active metabolites involved in the regulation of glucose metabolism in vivo. Single-dose administration of palmitoylcarnitine (PC) in fed mice induced marked insulin insensitivity, decreased glucose uptake in muscles, and elevated blood glucose levels. Increase in the content of LC acylcarnitine induced insulin resistance by impairing Akt phosphorylation at Ser473. The long-term administration of PC using slow-release osmotic minipumps induced marked hyperinsulinemia, insulin resistance, and glucose intolerance, suggesting that the permanent accumulation of LC acylcarnitines can accelerate the progression of insulin resistance. The decrease of acylcarnitine content significantly improved glucose tolerance in a mouse model of diet-induced glucose intolerance. In conclusion, we show that the physiological increase in content of acylcarnitines ensures the transition from a fed to fasted state in order to limit glucose metabolism in the fasted state. In the fed state, the inability of insulin to inhibit LC acylcarnitine production induces disturbances in glucose uptake and metabolism. The reduction of acylcarnitine content could be an effective strategy to improve insulin sensitivity. © 2017 BioFactors, 43(5):718-730, 2017.

Migratory birds act as hosts and long-distance vectors for several tick-borne infectious agents. Here, feeding Ixodes ticks were collected from migratory birds during the autumn migration period in Latvia and screened for the presence of epidemiologically important non-viral pathogens. A total of 93 DNA samples of ticks (37 larvae and 56 nymphs) removed from 41 birds (order Passeriformes, 9 species) was tested for Lyme borreliosis spirochaetes, Anaplasma phagocytophilum, Rickettsia spp., and Babesia spp. Borrelia burgdorferi DNA was detected in 18% of the tick samples, and a majority of infected ticks were from thrush (Turdus spp.) birds. Among the infected ticks, Borrelia valaisiana was detected in 41% of cases, Borrelia garinii in 35%, and mixed Bo. valaisiana and Bo. garinii infection in 24%. Anaplasma phagocytophilum DNA was detected in 2% of ticks, R. helvetica in 12%, and Babesia spp. pathogens in 4% of ticks. Among these samples, 3 Babesia species were identified: Ba. divergens, Ba. microti, and Ba. venatorum. Coinfection with different pathogens that included mixed infections with different Borrelia genospecies was found in 20% of nymphal and 3% of larval Ixodes ticks. These results suggest that migratory birds may support the circulation and spread of medically significant zoonoses in Europe.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent heart failure and decrease cardiovascular mortality in patients with type 2 diabetes. Heart failure is associated with detrimental changes in energy metabolism, and the preservation of cardiac mitochondrial function is crucial for the failing heart. However, to date, there are no data to support the hypothesis that treatment with a SGLT2 inhibitor might alter mitochondrial bioenergetics in diabetic failing hearts. Thus, the aim of this study was to investigate the protective effects of empagliflozin on mitochondrial fatty acid metabolism. Mitochondrial dysfunction was induced by 18 weeks of high-fat diet (HFD)-induced lipid overload. Empagliflozin was administered at a dose of 10 mg/kg in a chow for 18 weeks. Palmitate metabolism in vivo, cardiac mitochondrial functionality and biochemical parameters were measured. In HFD-fed mice, palmitate uptake was 1.7, 2.3, and 1.9 times lower in the heart, liver, and kidneys, respectively, compared with that of the normal chow control group. Treatment with empagliflozin increased palmitate uptake and decreased the accumulation of metabolites of incomplete fatty acid oxidation in cardiac tissues, but not other tissues, compared with those of the HFD control group. Moreover, empagliflozin treatment resulted in fully restored fatty acid oxidation pathway-dependent respiration in permeabilized cardiac fibers. Treatment with empagliflozin did not affect the biochemical parameters related to hyperglycemia or hyperlipidemia. Empagliflozin treatment preserves mitochondrial fatty acid oxidation in the heart under conditions of chronic lipid overload.