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Reducing infarct size during a cardiac ischaemic‐reperfusion episode is still of paramount importance, because the extension of myocardial necrosis is an important risk factor for developing heart failure. Cardiac ischaemia‐reperfusion injury (IRI) is in principle a metabolic pathology as it is caused by abruptly halted metabolism during the ischaemic episode and exacerbated by sudden restart of specific metabolic pathways at reperfusion. It should therefore not come as a surprise that therapy directed at metabolic pathways can modulate IRI. Here, we summarize the current knowledge of important metabolic pathways as therapeutic targets to combat cardiac IRI. Activating metabolic pathways such as glycolysis (eg AMPK activators), glucose oxidation (activating pyruvate dehydrogenase complex), ketone oxidation (increasing ketone plasma levels), hexosamine biosynthesis pathway (O‐GlcNAcylation; administration of glucosamine/glutamine) and deacetylation (activating sirtuins 1 or 3; administration of NAD+‐boosting compounds) all seem to hold promise to reduce acute IRI. In contrast, some metabolic pathways may offer protection through diminished activity. These pathways comprise the malate‐aspartate shuttle (in need of novel specific reversible inhibitors), mitochondrial oxygen consumption, fatty acid oxidation (CD36 inhibitors, malonyl‐CoA decarboxylase inhibitors) and mitochondrial succinate metabolism (malonate). Additionally, protecting the cristae structure of the mitochondria during IR, by maintaining the association of hexokinase II or creatine kinase with mitochondria, or inhibiting destabilization of FOF1‐ATPase dimers, prevents mitochondrial damage and thereby reduces cardiac IRI. Currently, the most promising and druggable metabolic therapy against cardiac IRI seems to be the singular or combined targeting of glycolysis, O‐GlcNAcylation and metabolism of ketones, fatty acids and succinate.

Increased plasma concentrations of acylcarnitines (ACs) are suggested as a marker of metabolism disorders. The aim of the present study was to clarify which tissues are responsible for changes in the AC pool in plasma. The concentrations of medium- and long-chain ACs were changing during the fed-fast cycle in rat heart, muscles and liver. After 60 min running exercise, AC content was increased in fasted mice muscles, but not in plasma or heart. After glucose bolus administration in fasted rats, the AC concentrations in plasma decreased after 30 min but then began to increase, while in the muscles and liver, the contents of medium- and long-chain ACs were unchanged or even increased. Only the heart showed a decrease in medium- and long-chain AC contents that was similar to that observed in plasma. In isolated rat heart, but not isolated-contracting mice muscles, the significant efflux of medium- and long-chain ACs was observed. The efflux was reduced by 40% after the addition of glucose and insulin to the perfusion solution. Overall, these results indicate that during fed-fast cycle shifting the heart determines the medium- and long-chain AC profile in plasma, due to a rapid response to the availability of circulating energy substrates.

Acute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies (‘IMPACT’), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit.

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.

Compounds, which rely on metabolism to exhibit toxicity, pose a challenge for next-generation risk assessment (NGRA). Since many of the currently available non-animal new approach methods (NAMs) lack metabolic activity, their use may lead to an underestimation of the true hazard to humans (false negative predictions). We explored here strategies to deal with metabolite-mediated toxicity in assays for developmental neurotoxicity. First, we present an overview of substances that may serve as potential positive controls for metabolite-related neurotoxicity. Then, we demonstrate, using the MitoMet (UKN4b) assay, which assesses the adverse effects of chemicals on neurites of human neurons, that some metabolites have a higher toxic potency than their parent compound. Next, we designed a strategy to integrate elements of xenobiotic metabolism into assays used for (developmental) neurotoxicity testing. In the first step of this approach, hepatic post-mitochondrial fractions (S9) were used to generate metabolite mixtures (“metabolisation module”). In the second step, these were applied to a NAM (exemplified by the UKN4b assay) to identify metabolite-mediated toxicity. We demonstrate the applicability and transferability of these approaches to other assays, by an exemplary study on the basis of the cMINC (UKN2) assay, another NAM of the developmental neurotoxicity in vitro battery. Based on the experience gained from these experiments, we discuss key issues to be addressed if this approach is to be used more broadly for NAM in the NGRA context.

Deletion of exon 2 of the trimethyllysine hydroxylase epsilon ( TMLHE ) gene was identified in probands with autism spectrum disorder (ASD). TMLHE encodes the first enzyme in carnitine biosynthesis, N6-trimethyllysine dioxygenase (TMLD). Researchers have suggested that carnitine depletion could be important for the development of ASD and cognitive, locomotor and social dysfunctions, but previous findings have been inconclusive regarding the specific role of endogenous carnitine. We developed a mouse knockout model with constitutive TMLD enzyme inactivation that exhibited a significant decrease in the carnitine by more than 90% compared to wild-type (WT) mice. However, we did not observe any significant social, cognitive, or repetitive-behavior changes associated with ASD in the knockout mice; muscle strength and coordination were also not affected. In addition, the life expectancy of knockout mice was similar to that of WT mice. In conclusion, knockout of Tmlh in mice does not induce an ASD phenotype or motor dysfunction despite extremely low carnitine and gamma-butyrobetaine concentrations. Moreover, inactivation of TMLD does not induce a phenotype similar to previously described primary carnitine deficiency; indeed, our results showed that low levels of carnitine sustained adequate energy production, muscle function and social behavior in mice.

Aim Exercise training induces adaptations in muscle and other tissue mitochondrial metabolism, dynamics, and oxidative phosphorylation capacity. Mitochondrial fatty acid oxidation was shown to be pivotal for the anti‐inflammatory status of immune cells. We hypothesize that exercise training can exert effects influence mitochondrial fatty acid metabolism in peripheral blood mononuclear cells (PBMCs). The aim was to investigate the effect of exercise on the fatty acid oxidation‐dependent respiration in PBMCs. Design Twelve fasted or fed volunteers first performed incremental‐load exercise tests to exhaustion on a cycle ergometer to determine the optimal workload ensuring maximal health benefits in volunteers with a sedentary lifestyle. In addition, the same volunteers performed 60 min of low‐intensity constant‐load exercise. Results In the incremental‐load exercise, the maximal whole‐body fat oxidation rate measured by indirect calorimetry was reached at the fasted state already at a 50 W workload. At the 75–175 W workloads, the contribution of fat oxidation significantly decreased to only 11%, the heart rate increased to 185 BPM, and the study participants reached exhaustion. These results show that low‐intensity exercise (50W) is optimal for maximal whole‐body fat utilization. After low‐intensity exercise, the ROUTINE mitochondrial respiration, as well as fatty acid oxidation‐dependent respiration in PBMCs at LEAK and OXPHOS states, were significantly increased by 31%, 65%, and 76%, respectively. In addition, during 60 min of low‐intensity (50W) exercise, a 2‐fold higher lipolysis rate was observed and 13.5 ± 0.9 g of fat was metabolized, which was 57% more than the amount of fat that was metabolized during the incremental‐load exercise. Conclusions In individuals with a sedentary lifestyle participating in a bicycle ergometry exercise program, maximal lipolysis and whole‐body fat oxidation rate is reached in a fasted state during low‐intensity exercise. For the first time, it was demonstrated that low‐intensity exercise improves bioenergetics and increases fatty acid oxidation in PBMCs and may contribute to the anti‐inflammatory phenotype.

Birch outer bark extract (BBE), containing pentacyclic triterpenes such as betulin, lupeol, and betulinic acid, is a widely recognized natural product renowned for its diverse pharmacological effects. However, its limited water solubility restricts its bioavailability. Therefore, the main objective is to enhance the bioavailability of BBE for pharmaceutical use. In this study, we aimed to develop a dispersion system utilizing a unique oleogel-producing method through the recrystallization of BBE from an ethanol solution in the oil phase. We generated an oleogel that demonstrates a notable 42–80-fold improvement in betulin and lupeol peroral bioavailability from BBE in Wistar rats, respectively. A physical paste-like BBE hydrogel developed with antisolvent precipitation showed a 16–56-fold increase in the bioavailability of betulin and lupeol from BBE in rat blood plasma, respectively. We also observed that the repeated administration of the BBE oleogel did not exhibit any toxicity at the tested dose (38.5 mg/kg betulin, 5.2 mg/kg lupeol, 1.5 mg/kg betulinic acid daily for 7 days). Betulin and betulinic acid were not detected in rat heart, liver, kidney, or brain tissues after the peroral administration of the oleogel daily for 7 days. Lupeol was found in rat heart, liver, and kidney tissues.

Many drug candidates have shown significant renoprotective effects in preclinical models; however, there is no clinically used effective pharmacotherapy for acute kidney injury. The failure to translate from bench to bedside could be due to misleading results from experimental animals with undetected congenital kidney defects. This study was performed to assess the effects of congenital hydronephrosis on the functional capacity of tubular renal transporters as well as kidney sensitivity to ischemia‐reperfusion (I‐R)‐induced injury in male Wistar rats. Ultrasonography was used to distinguish healthy control rats from rats with hydronephrosis. L‐carnitine or furosemide was administered, and serial blood samples were collected and analyzed to assess the effects of hydronephrosis on the pharmacokinetic parameters. Renal injury was induced by clamping the renal pedicles of both kidneys for 30 min with subsequent 24 hr reperfusion. The prevalence of hydronephrosis reached ~30%. The plasma concentrations after administration of L‐carnitine or furosemide were similar in both groups. I‐R induced more pronounced renal injury in the hydronephrotic rats than the control rats, which was evident by a significantly higher kidney injury molecule‐1 concentration and lower creatinine concentration in the urine of the hydronephrotic rats than the control rats. After I‐R, the gene expression levels of renal injury markers were significantly higher in the hydronephrotic kidneys than in the kidneys of control group animals. In conclusion, our results demonstrate that hydronephrotic kidneys are more susceptible to I‐R‐induced damage than healthy kidneys. Unilateral hydronephrosis does not affect the pharmacokinetics of substances secreted or absorbed in the renal tubules. Hydronephrotic kidneys are more susceptible to I‐R‐induced damage than healthy kidneys.