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Treatment of the most aggressive and deadliest form of skin cancer, the malignant melanoma, still has room for improvement. Its invasive nature and ability to rapidly metastasize and to develop resistance to standard treatment often result in a poor prognosis. While the highly effective standard chemotherapeutic agent doxorubicin (DOX) is widely used in a variety of cancers, systemic side effects still limit therapy. Especially, DOX-induced cardiotoxicity remains a big challenge. In contrast, the natural chalcone cardamonin (CD) has been shown to selectively kill tumor cells. Besides its anti-tumor activity, CD exhibits anti-oxidative, anti-inflammatory and anti-bacterial properties. In this study, we investigated the effect of the combinational treatment of DOX with CD on A375 melanoma cells compared to normal human dermal fibroblasts (NHDF) and rat cardiac myoblasts (H9C2 cells). DOX-induced cytotoxicity was unselective and affected all cell types, especially H9C2 cardiac myoblasts, demonstrating its cardiotoxic effect. In contrast, CD only decreased the cell viability of A375 melanoma cells, without harming normal (healthy) cells. The addition of CD selectively protected human dermal fibroblasts and rat cardiac myoblasts from DOX-induced cytotoxicity. While no apoptosis was induced by the combinational treatment in normal (healthy) cells, an apoptosis-mediated cytotoxicity was demonstrated in A375 melanoma cells. CD exhibited thiol reactivity as it was able to directly interact with N-acetylcysteine (NAC) in a cell-free assay and to induce heme oxygenase-1 (HO-1) in all cell types. And that took place in a reactive oxygen species (ROS)-independent manner. DOX decreased the mitochondrial membrane potential (Δψ m ) in all cell types, whereas CD selectively decreased mitochondrial respiration, affecting basal respiration, maximal respiration, spare respiratory capacity and ATP production in A375 melanoma cells, but not in healthy cardiac myoblasts. The DOX-induced cytotoxicity seen in melanoma cells was ROS-independent, whereas the cytotoxic effect of CD was associated with CD-induced ROS-formation and/or its thiol reactivity. This study highlights the beneficial properties of the addition of CD to DOX treatment, which might protect patients from DOX-induced cardiotoxicity. Future experiments with other tumor cell lines or a mouse model should substantiate this hypothesis.

Background: Malignant melanoma is the most aggressive form of skin cancer with a rather poor prognosis. Standard chemotherapy often results in severe side effects on normal (healthy) cells finally being difficult to tolerate for the patients. Shown by us earlier, cerium oxide nanoparticles (CNP, nanoceria) selectively killed A375 melanoma cells while not being cytotoxic at identical concentrations on non-cancerous cells. In conclusion, the redox-active CNP exhibited both prooxidative as well as antioxidative properties. In that context, CNP induced mitochondrial dysfunction in the studied melanoma cells via generation of reactive oxygene species (primarily hydrogen peroxide (H2O2)), but that does not account for 100% of the toxicity., Aim: Cancer cells often show an increased glycolytic rate (Warburg effect), therefore we focused on CNP mediated changes of the glucose metabolism., Results: It has been shown before that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity is regulated via oxidation of a cysteine in the active center of the enzyme with a subsequent loss of activity. Upon CNP treatment, formation of cellular lactate and GAPDH activity were significantly lowered. The treatment of melanoma cells and melanocytes with the GAPDH inhibitor heptelidic acid (HA) decreased viability to a much higher extent in the cancer cells than in the studied normal (healthy) cells, highlighting and supporting the important role of GAPDH in cancer cells., Conclusion: We identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a target protein for CNP mediated thiol oxidation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 von Montfort et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neuroblastoma is the most common extracranial malignant tumor in childhood. Approximately 60% of all patients are classified as high-risk and require intensive treatment including non-selective chemotherapeutic agents leading to severe side effects. Recently, phytochemicals like the natural chalcone cardamonin (CD) have gained attention in cancer research. For the first time, we investigated the selective anti-cancer effects of CD in SH-SY5Y human neuroblastoma cells compared to healthy (normal) fibroblasts (NHDF). Our study revealed selective and dose-dependent cytotoxicity of CD in SH-SY5Y. The natural chalcone CD specifically altered the mitochondrial membrane potential (ΔΨm), as an early marker of apoptosis, in human neuroblastoma cells. Caspase activity was also selectively induced and the amount of cleaved caspase substrates such as PARP was thus increased in human neuroblastoma cells. CD-mediated apoptotic cell death was rescued by pan caspase inhibitor Z-VAD-FMK. The natural chalcone CD selectively induced apoptosis, the programmed cell death, in SH-SY5Y human neuroblastoma cells whereas NHDF being a model for normal (healthy) cells were unaffected. Our data indicates a clinical potential of CD in the more selective and less harmful treatment of neuroblastoma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Despite great efforts to develop new therapeutic strategies to combat melanoma, the prognosis remains rather poor. Artesunate (ART) is an antimalarial drug displaying anti-cancer effects in vitro and in vivo. In this in vitro study, we investigated the selectivity of ART on melanoma cells. Furthermore, we aimed to further elucidate the mechanism of the drug with a focus on the role of iron, the induction of oxidative stress and the implication of the enzyme heme oxygenase 1 (HO-1). ART treatment decreased the cell viability of A375 melanoma cells while it did not affect the viability of normal human dermal fibroblasts, used as a model for normal (healthy) cells. ART's toxicity was shown to be dependent on intracellular iron and the drug induced high levels of oxidative stress as well as upregulation of HO-1. Melanoma cells deficient in HO-1 or treated with a HO-1 inhibitor were less sensitive towards ART. Taken together, our study demonstrates that ART induces oxidative stress resulting in the upregulation of HO-1 in melanoma cells, which subsequently triggers the effect of ART's own toxicity. This new finding that HO-1 is involved in ART-mediated toxicity may open up new perspectives in cancer therapy.

Cutaneous basal and squamous cell carcinoma reflect the first and second most common type of non-melanoma skin cancer, respectively. Especially cutaneous squamous cell carcinoma has the tendency to metastasize, finally resulting in a rather poor prognosis. Therapeutic options comprise surgery, radiation therapy, and a systemic or targeted chemotherapy. There are some good treatment results, but overall, the response rate of newly developed drugs is still modest. Drug repurposing represents an alternative approach where already available and clinically approved substances are used, which originally intended for other clinical benefits. In this context, we tested the effect of the naturally occurring polyphenolic aldehyde (±) gossypol with concentrations between 1 and 5 µM on the invasive squamous cell carcinoma cell line SCL-1 and normal human epidermal keratinocytes. Gossypol treatment up to 96 h resulted in a selective cytotoxicity of SCL-1 cells (IC 50 : 1.7 µM, 96 h) compared with normal keratinocytes (IC 50 : ≥ 5.4 µM, 96 h) which is mediated by mitochondrial dysfunction and finally leading to necroptotic cell death. Taken together, gossypol shows a high potential as an alternative anticancer drug for the treatment of cutaneous squamous cell carcinoma., (© 2023. The Author(s).)

Introduction: Transvenous implantable cardioverter-defibrillator (ICD) shocks have been associated with cardiac biomarker elevations and are thought in some cases to contribute to adverse clinical outcomes and mortality, possibly from myocardium exposed to excessive shock voltage gradients. Currently, there are only limited data for comparison with subcutaneous ICDs. We sought to compare ventricular myocardium voltage gradients resulting from transvenous (TV) and subcutaneous defibrillator (S-ICD) shocks to assess their risk of myocardial damage., Methods: A finite element model was derived from thoracic magnetic resonance imaging (MRI). Voltage gradients were modeled for an S-ICD with a left-sided parasternal coil and a left-sided TV-ICD with a mid-cavity, a septal right ventricle (RV) coil, or a dual coil lead (TV mid, TV septal, TV septal +  superior vena cava [SVC]). High gradients were defined as > 100 V/cm., Results: The volumes of ventricular myocardium with high gradients > 100 V/cm were 0.02, 2.4, 7.7, and 0 cc for TV mid, TV septal, TV septal + SVC, and S-ICD, respectively., Conclusion: Our models suggest that S-ICD shocks produce more uniform gradients in the myocardium, with less exposure to potentially damaging electrical fields, compared to TV-ICDs. Dual coil TV leads yield higher gradients, as does closer proximity of the shock coil to the myocardium., (© 2023 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Carbon monoxide (CO) is endogenously produced upon degradation of heme by heme oxygenases (HOs) and is suggested to act as a gaseous signaling molecule. The expression of HO-1 is triggered by the Nrf2-Keap1 signaling pathway which responds to exogenous stress signals and dietary constituents such as flavonoids and glucosinolates or reactive metabolic intermediates like 4-hydroxynonenal. Endogenous CO affects energy metabolism, regulates the utilization of glucose and addresses CYP450 enzymes. Using the CO releasing molecule-401 (CORM-401), we studied the effect of endogenous CO on ATP synthesis, AMP-signaling and activation of the AMPK pathway in cell culture. Upon exposure of cells to CORM-401, the mitochondrial ATP production rate was significantly decreased (P=0.007) to about 50%, while glycolytic ATP synthesis was unchanged (P=0.489). Total ATP levels were less affected as determined by mass spectrometry. Instead, levels of ADP and AMP were elevated following CORM-401 exposure by about two- (P=0.022) and four-fold (P=0.012) compared to control, respectively. Increased concentrations of AMP activate AMPK which was demonstrated by a 10 to 15-fold increased phosphorylation of Thr172 of the α-subunit of AMPK (P=0.025). A downstream target of AMPK is the kinase ULK1 which triggers autophagic and mitophagic processes. Activation of ULK1 after CO exposure was proven by a 3 to 5-fold elevated phosphorylation of ULK1 at Ser555 (P=0.004). The present data suggest that production of endogenous CO leads to increasing amounts of AMP which mediates AMPK-dependent downstream effects and likely triggers autophagic processes. Since dietary constituents and their metabolites induce the expression of the CO producing enzyme HO-1, CO signaling may also be involved in the cellular response to nutritional factors.

High-resolution spectroscopy techniques play a pivotal role to validate and efficiently benchmark available methods from quantum chemistry. In this work, we analyzed the microwave spectrum of ethyl butyrate within the scope of a systematic investigation to benchmark state-of-the-art exchange-correlation functionals and ab initio methods, to accurately predict the lowest energy conformers of carbonyl compounds in their isolated state. Under experimental conditions, we observed two distinct conformers, one of C s and one of C 1 symmetry. As reported earlier in the cases of some ethyl and methyl alkynoates, structural optimizations of the most abundant conformer that exhibits a C 1 symmetry proved extremely challenging for several quantum chemical levels. To probe the sensitivity of different methods and basis sets, we use the identified soft-degree of freedom in proximity to the carbonyl group as an order parameter. The results of our study provide useful insight for spectroscopists to select an adapted method for structure prediction of carbonyl compounds based on their available computational resources, suggesting a reasonable trade-off between accuracy and CPU cost. At the same time, our observations and the resulting sets of highly accurate experimental constants from high-resolution spectroscopy experiments give an appeal to theoretical groups to look further into this seemingly simple family of chemical compounds, which may prove useful for the further development and parametrization of theoretical methods in computational chemistry.

Background: Preventive lifestyle strategies have shown promise to slow down or prevent age-related cognitive decline. However, evidence on the reciprocal longitudinal relationships between nutrition biomarkers and cognitive and physical performance is lacking. Studying nutritional, cognitive, and physical profiles over time may help to overcome this knowledge gap., Objective: To investigate the relationship of plasma levels of the robust nutritional- and antioxidant defense-related biomarkers carotenoids and tocopherols with both indicators of cognitive and physical performance in persons with mild cognitive impairment (MCI) participating in a structured exercise program., Methods: Data from 40 participants with MCI of the NeuroExercise study were analyzed. Participants had undergone a blood withdrawal for the analysis of plasma concentrations of six carotenoids, two tocopherols and retinol prior to and after one-year of structured exercise. All participants had undergone a broad spectrum of cognitive and physical performance tests., Results: Significant associations between lipophilic micronutrients and cognitive/physical measures were observed that were previously found to play a role in cognitive and physical frailty. In particular, lutein, zeaxanthin, and lycopene are confirmed as robust, reliable, and stable indicators of nutritional defense. Importantly, these micronutrients were associated with cognitive measures prior to the physical training program and to a more prominent extent with indicators of motoric function after the physical exercise program., Conclusion: Specific profiles of lipophilic micronutrients are associated to cognitive performance measures and, especially after a structured exercise program, to indicators of physical performance., Competing Interests: The authors declare no conflict of interest. The funders (EU JPND) had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© 2022 – The authors. Published by IOS Press.)

Background: Electronic products, including the iPhone 12, Apple Watch Series 6, and 2nd Generation AirPods, contain magnets to facilitate wireless charging. Permanent magnets may affect CIED magnet mode features by causing pacemakers to pace asynchronously and defibrillators to suspend arrhythmia detection. This study determined if CIEDs are affected by static magnetic fields from commonly used portable electronics (PE) at any distance and intends to reinforce FDA recommendations concerning consumer PE which contain permanent magnets., Methods: The maximum magnet field measurement was evaluated by a Gauss meter. The interaction between PE and CIEDs from Boston Scientific and Medtronic were tested ex vivo using a body torso model. The CIED was placed in physiologic saline, and the PE was placed at the surface and at increasing distances of 0.5, 1.0, and 1.5 cm. Interactions were recorded by assessment of magnet mode status., Results: The iPhone 12 had almost three times the static magnetic field measured at the surface as the iPhone XR, but magnetic field strength decreased dramatically with increasing distance. At the surface of the model, PE triggered magnet mode in all CIEDs. The maximum interaction distance for all combinations of CIEDs and Apple products was 1.5 cm., Conclusions: The iPhone 12 produces a stronger static magnetic field than previous iPhone models. Magnets in PE tested will not interact with CIEDs when they are 15 cm from the implanted device. Since no interaction was observed beyond 1.5 cm, it is unlikely that magnet mode activation will occur during most daily activities., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The rotational spectrum of phenyl acetate, CH 3 COOC 6 H 5 , is measured using a free jet absorption millimeter-wave spectrometer in the range from 60 to 78 GHz and two pulsed jet Fourier transform microwave spectrometers covering a total frequency range from 2 to 26.5 GHz. The features of two large amplitude motions, the methyl group internal rotation and the skeletal torsion of the CH 3 COO group with respect to the phenyl ring C 6 H 5 (tilted at about 70°), characterize the spectrum. The vibrational ground state is split into four widely spaced sublevels, labeled as A0, E0, A1, and E1, each of them with its set of rotational transitions and with additional interstate transitions. A global fit of the line frequencies of the four sublevels leads to the determination of 51 spectroscopic parameters, including the Δ E A0/A1 and Δ E E0/E1 vibrational splittings of ~36.4 and ~33.5 GHz, respectively. The V 3 barrier to methyl internal rotation (~136 cm -1 ) and the skeletal torsion B 2 barrier to the orthogonality of the two planes (~68 cm -1 ) are deduced.

Objective: To investigate the association of dental and cardiac disease in a cohort of captive chimpanzees DESIGN: 12 captive chimpanzees underwent periodontal and cardiac examinations under anaesthesia during a relocation to a new enclosure. Blood samples were taken for analysis of circulating markers of cardiac health, nutritional status and isolation of neutrophils for functional assays. They were then observed for three years for signs of heart disease., Results: Although the chimpanzees displayed large quantities of supragingival plaque, they had low bleeding scores. Peripheral blood neutrophils responded to innate and adaptive immune stimuli. In the follow up period two animals died and post mortem confirmed heart disease. Levels of NT-proBNP were found to be high in chimpanzees that died from heart disease., Conclusions: Whilst there appeared to be a correlation between probing depth and age, there appeared to be no correlation between dental data and heart data in this cohort., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The term "nutritional cognitive neuroscience" was recently established to define a research field focusing on the impact of nutrition on cognition and brain health across the life span. In this overview, we summarize the robust evidence on the role of carotenoids as micronutrients with different biological properties in persons with cognitive (pre)frailty. As neurodegenerative processes during aging occur in a continuum from brain aging to dementia, we propose the name "nutritional cognitive neuroscience of aging" to define research on the role of nutrition and micronutrients in cognitive frailty. Further studies are warranted which integrate carotenoid interventions in multidomain, personalized lifestyle strategies., (Copyright © 2021. Published by Elsevier B.V.)

The microwave spectrum of 2,5-dimethylpyrrole was recorded using a molecular jet Fourier transform microwave spectrometer operating in the frequency range from 2 to 26.5 GHz. Only one stable conformer was observed as expected and confirmed by quantum chemical calculations carried out to complement the experimental analysis. The two equivalent methyl groups cause each rotational transition to split into four torsional species, which is combined with the quadrupole hyperfine splittings in the same order of magnitude arising from the 14 N nucleus. This results in a complicated spectrum feature. The spectral assignment was done separately for each torsional species. Two global fits were carried out using the XIAM code and the BELGI-C 2v -2Tops-hyperfine code, a modified version of the BELGI-C 2v -2Tops code, giving satisfactory root-mean-square deviations. The potential barriers to internal rotation of the two methyl groups were determined to be V 3 = 317.208(16) cm -1 . The molecular parameters were obtained with high accuracy, providing all necessary ground state information for further investigations in higher frequency ranges and on excited torsional-vibrational states.

A major challenge in current cancer therapy is still the treatment of metastatic melanomas of the skin. BH3 mimetics represent a novel group of substances inducing apoptosis. In this study, we investigated the cytotoxic effect of (±) gossypol (GP), a natural compound from cotton seed, on A375 melanoma cells and the underlying biochemical mechanisms. To prevent undesired side effects due to toxicity on normal (healthy) cells, concentrations only toxic for tumor cells have been elaborated. Viability assays were performed to determine the cytotoxicity of GP in A375 melanoma and normal (healthy) cells. For the majority of experiments, a concentration of 2.5 µM GP was used resulting in a ROS-independent but caspase-dependent cell death of A375 melanoma cells. At this level, GP was non-toxic for normal human epidermal melanocytes. GP has a very short half-life, however, it was demonstrated that only the "parent" compound and not decomposition products are responsible for the cytotoxic effect in A375 melanoma cells. GP significantly decreased mitochondrial membrane potential accompanied by a Drp1-dependent loss of mitochondrial integrity (fragmentation) in tumor cells. Taken together, GP induced a ROS-independent intrinsic apoptosis leading to the conclusion that within a specific concentration range, GP may work as effective anticancer drug without harmful side effects.

The microwave spectrum of the fruit ester methyl valerate was recorded using two molecular jet Fourier transform spectrometers covering the frequency range from 2 to 40 GHz. Quantum chemical calculations yielded 11 minima for the anti ester configuration, among them two were identified in the experimental spectrum. The methyl group in the methoxy moiety undergoes internal rotation, leading to torsional splittings of all rotational transitions into doublets. The barrier to internal rotation of the methoxy methyl group was deduced to be 417.724(70) cm-1 and 418.059(27) cm-1 for the C1 and the Cs conformer, respectively, essentially the same values as those in methyl alkanoates with shorter alkyl chains, which are methyl acetate, methyl propionate and methyl butyrate. Geometry parameters such as the rotational and centrifugal distortion constants could be determined with very high accuracy. Optimisations at different levels of theory were performed for a comparison with the experimental results. The MP2/6-311++G(d,p) level of theory failed to calculate reliable rotational constants to guide the assigment of the C1 conformer, while the MP2/cc-pVDZ level fully succeeded.

Selenoenzymes, whose activity depends on adequate selenium (Se) supply, and phase II enzymes, encoded by target genes of nuclear factor erythroid 2-related factor 2 (Nrf2), take part in governing cellular redox homeostasis. Their interplay is still not entirely understood. Here, we exposed HepG2 hepatoma cells cultured under Se-deficient, Se-adequate, or Se-supranutritional conditions to the Nrf2 activators sulforaphane, cardamonin, or diethyl maleate. Nrf2 protein levels and intracellular localization were determined by immunoblotting, and mRNA levels of Nrf2 target genes and selenoproteins were assessed by qRT-PCR. Exposure to electrophiles resulted in rapid induction of Nrf2 and its enrichment in the nucleus, independent of the cellular Se status. All three electrophilic compounds caused an enhanced expression of Nrf2 target genes, although with differences regarding extent and time course of their induction. Whereas Se status did not significantly affect mRNA levels of the Nrf2 target genes, gene expression of selenoproteins with a low position in the cellular "selenoprotein hierarchy", such as glutathione peroxidase 1 (GPX1) or selenoprotein W (SELENOW), was elevated under Se-supplemented conditions, as compared to cells held in Se-deficient media. In conclusion, no major effect of Se status on Nrf2 signalling was observed in HepG2 cells.

The spectra of N-ethyl methyl amine, CH 3 (NH)CH 2 CH 3 , were measured using a molecular jet Fourier transform microwave spectrometer in the frequency range of 2 GHz-26.5 GHz. Splittings due to proton inversion tunneling, Coriolis coupling, 14 N quadrupole coupling, and methyl internal rotation were fully resolved. The experimentally deduced rotational constants are A = 25 934.717(21) MHz, B = 3919.8212(23) MHz, and C = 3669.530(21) MHz. The proton tunneling causes (+) ↔ (-) splittings of about 1980.9 MHz for all c-type transitions between the lowest symmetric and the higher anti-symmetric energy levels. The splittings of the (+) ← (+) and (-) ← (-) levels, mainly influenced by Coriolis coupling, were also observed and assigned for b-type transitions, yielding the coupling constants F bc = 0.3409(71) MHz and F ac = 163.9(14) MHz. The 14 N quadrupole coupling constants were determined to be χ aa = 2.788 65(55) MHz and χ bb - χ cc = 4.630 45(91) MHz. Fine splittings arising from two inequivalent methyl rotors are in the order of 150 kHz, and the torsional barriers are determined to be 1084.62(41) cm -1 for the CH 3 NH methyl group and 1163.43(80) cm -1 for the CH 2 CH 3 methyl group. The experimental results are in good agreement with those of quantum chemical calculations.

The skin is shielding our organism from exogenous threats including solar radiation. Carotenoids which are ingested with the diet accumulate in the skin with the highest levels occurring in skin of the forehead and in the palms of the hands. Blood and skin levels of carotenoids increase during supplementation and due to their antioxidant properties and UV-absorbing effects carotenoids are used as photoprotective agents. Systemic photoprotection with carotenoids after supplementation or ingestion of a carotenoid rich diet has been demonstrated in several human intervention studies. Although protection is only moderate it may contribute to UV protection in combination with other measures. Beyond photoprotection, ingestion of carotenoids has been postulated to be of additional benefit for cutaneous tissue and influences moisture and texture or elasticity of the skin. However, only a limited number of studies is available yet to substantiate such a claim., Competing Interests: Declaration of Competing Interest Research of WS has been funded by the Deutsche Forschungsgemeinschaft Project STA 699/3-1, (Copyright © 2019 Elsevier B.V. All rights reserved.)

Carbon monoxide (CO) intoxication is one of the most frequent causes of accidental poisoning, mechanistically related to the inhibition of oxygen transport following blockage of the oxygen binding site of hemoglobin. However, it has become evident that CO is also a gaseous signaling molecule like nitric oxide and capable to trigger cellular stress responses in complex organisms. Endogenously, CO is synthesized upon degradation of heme by heme oxygenases (HOs) of which two enzymatically active isoenzymes are known in mammals; the stress-inducible HO-1 and the constitutively expressed HO-2. Among other pathways, HO-1 expression is stimulated by the Nrf2/Keap1 system which senses electrophilic compounds including alkylating agents and reactive oxygen species (ROS) such as superoxide or hydrogen peroxide. In context with ROS, HO-1 expression has been associated with antioxidant defense related to the heme-metabolite redox pair biliverdin/bilirubin. Studies on CO signaling were facilitated by the introduction of so called "CO releasing molecules" (CORMs), which allow for the controlled release of the compound in biological systems. Obviously, major biological targets of CO comprise intracellular heme-proteins such as cytochrome c oxidase of the respiratory chain, cytochrome P450-dependent monooxygenases (CYPs), or NADPH oxidases. From toxicological studies it is known that exposure to high amounts of CO provokes an inhibition of mitochondrial respiration and increased generation of ROS. In contrast, biological response to low amounts of CO comprises moderate mitochondrial uncoupling (proton leakage) due to the activation of channels including phosphate carrier (P i C), adenine nucleotide translocase (ANT) or large-conductance Ca 2+ -activated K + channels (BK Ca ). Uncoupling of mitochondrial respiration from ATP production is accompanied by a loss of mitochondrial membrane potential - a key sensor and regulator of mitochondrial quality control and mitophagy. Inhibitory effects of CO on mitochondrial respiration are compensated by an increased glycolysis. However, on a short term, utilization of glucose is shifted to the pentose phosphate pathway, to provide NADPH for detoxification. It is notable that endogenous CO production is associated with the physiological response against exogenous electrophilic insult like Nrf2-dependent expression of phase II enzymes or glutathione synthesis. In contrast phase I enzymes such as CYPs which usually generate more electrophiles are inhibited by CO. Together with direct and indirect transient effects on energy metabolism and mitochondrial quality control CO may be an important regulator in cellular stress response., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Methyl n-alkyl ketones form a class of molecules with interesting internal dynamics in the gas-phase. They contain two methyl groups undergoing internal rotations, the acetyl methyl group and the methyl group at the end of the alkyl chain. The torsional barrier of the acetyl methyl group is of special importance, since it allows for the discrimination of the conformational structures. As part of the series, the microwave spectrum of octan-2-one was recorded in the frequency range from 2 to 40 GHz, revealing two conformers, one with C 1 and one with C s symmetry. The barriers to internal rotation of the acetyl methyl group were determined to be 233.340(28) cm -1 and 185.3490(81) cm -1 , respectively, confirming the link between conformations and barrier heights already established for other methyl alkyl ketones. Extensive comparisons to molecules in the literature were carried out, and a small overview of general trends and rules concerning the acetyl methyl torsion is given. For the hexyl methyl group, the barrier height is 973.17(60) cm -1 for the C 1 conformer and 979.62(69) cm -1 for the C s conformer., (© 2020 Wiley-VCH GmbH.)

Chalcones are a type of flavonoids characterized by an α-β unsaturated structural element which may react with thiol groups to activate pathways such as the Nrf2-Keap-1 system. Naringenin chalcone is abundant in the diet but little is known about its bioavailability. In this work, the bioavailability of naringenin chalcone from tomatoes was investigated in a group of healthy men (n=10). After ingestion of 600 grams of tomatoes providing a single dose of 17.3 mg naringenin chalcone, 0.2 mg of naringenin, and 195 mg naringin plasma levels of free and conjugated naringenin and naringenin chalcone (glucuronide and sulfate) were analyzed by UHPLC-QTOF-MS at 0.5, 1, 3, and 6 h post-consumption. Plasma levels of conjugated naringenin increased to about 12 nmol/L with a maximum at about 3 h. Concentrations of free naringenin hardly elevated above baseline. Plasma levels of free and conjugated naringenin chalcone significantly increased. A maximum of the conjugated chalcone was reached at about 3 h after ingestion with an average concentration of about 0.5 nmol/L. No free chalcone was detectable at baseline but low amounts of the unconjugated compound could be detected with an average maximum of 0.8 nmol/L at about 1 h after ingestion. The data demonstrate that naringenin chalcone is bioavailable in humans from cherry tomatoes as a dietary source. However, availability is poor and intramolecular cyclisation as well as extended metabolism likely contribute to the inactivation of the reactive alpha-beta unsaturated reactive center as well as the excretion of the biologically active molecule, respectively.

The long-standing ambiguity of the molecular planarity when an alkyl group is attached to a system with conjugated double bonds is a great challenge for both experiments and theory. This also holds true for the case of 2-propionylthiophene (2PT) where a propionyl group is attached at the second position of the planar, aromatic thiophene ring. Results from quantum chemistry at the MP2 level of theory, showing that in the two conformers syn- and anti-2PT the ethyl group of the propionyl moiety is slightly tilted out of the thiophene ring plane, conflict with those from the other methods, stating that the ethyl group is in-plane with the thiophene ring. In the microwave spectrum, both syn- and anti-2PT were observed, and their geometry parameters such as the rotational and quartic centrifugal distortion constants were precisely determined. The experimental heavy atom skeleton obtained by isotopic substitutions revealed a tiny, but non-zero tilt angle of the ethyl group out of the thiophene plane, thereby convincingly confirming the non-planarity of 2-propionylthiophene. This conclusion was further supported by the inertial defects calculated from the experimental rotational constants. Finally, splittings arising from the internal rotation of the terminal methyl group were analysed, yielding torsional barriers of 806.94(54) cm-1 and 864.5(88) cm-1 for the two observed conformers, respectively.

Stress-inducible heme oxygenase-1 (HO-1) catalyzes the oxidative cleavage of heme yielding biliverdin, ferrous iron, and carbon monoxide (CO). Heme oxygenase activity has been attributed to antioxidant defense via the redox cycling system of biliverdin and bilirubin. There is increasing evidence that CO is a gaseous signaling molecule and plays a role in the regulation of energy metabolism. Inhibitory effects of CO on the respiratory chain are well established, but the implication of such a process on the cellular stress response is not well understood. By means of extracellular flux analyses and isotopic tracing, we studied the effects of CO, either released from the CO donor CORM-401 or endogenously produced by heme oxygenases, on the respiratory chain and glucose metabolism. CORM-401 was thereby used as a tool to mimic endogenous CO production by heme oxygenases. In the long term (>60 min), CORM-401-derived CO exposure inhibited mitochondrial respiration, which was compensated by increased glycolysis accompanied by a loss of the ATP production rate and an increase in proton leakage. This effect pattern was likewise observed after endogenous CO production by heme oxygenases. However, in the present setting, these effects were only observed when sufficient substrate for heme oxygenases (hemin) was provided. Modulation of the HO-1 protein level was less important. The long-term influence of CO on glucose metabolism via glycolysis was preceded by a short-term response (<30 min) of the cells to CO. Stable isotope-labeling experiments and metabolic flux analysis revealed a short-term shift of glucose consumption from glycolysis to the pentose phosphate pathway (PPP) along with an increase in reactive oxygen species (ROS) generation. Overall, we suggest that signaling by endogenous CO stimulates the rapid formation of reduction equivalents (NADPH) via the PPP, and plays an additional role in antioxidant defense, e.g., via feed-forward stimulation of the bilirubin/biliverdin redox cycling system.

Intracellular carbon monoxide (CO) is a gaseous signaling molecule and is generated enzymatically by heme oxygenases upon degradation of heme to billiverdin. Target structures for intracellular produced CO are heme proteins including cytochrome c oxidase of the respiratory chain, cytochrome P450-dependent monooxygenases, or myoglobin. For studies on CO signaling, CO-releasing molecules (CORMs) of different structure are available. Here, three frequently used CORMs (CORM-2, CORM-3 and CORM-401) were studied for their properties to provide CO in biological test systems and address susceptible heme proteins. CO release was investigated in the myoglobin binding assay and found to be rapid (<5 min) with CORM-2- and CORM-3, whereas CORM-401 continuously provided CO (>50 min). Storage stability of CORM stock solutions was also assessed with the myoglobin assay. Only CORM-401 stock solutions were stable over a period of 7 days. Incubation of CORMs with recombinant cytochrome P450 led to an inhibition of enzyme activity. However, only CORM-3 and CORM-401 proved to be suitable in this test system because controls with the inactivated CORM-2 (iCORM-2) also led to a loss of enzyme activity. The impact of CORMs on the respiratory chain was investigated with high resolution respirometry and extracellular flux technology. In the first approach interferences of CORM-2 and CORM-3 with oxygen measurement occurred, since a rapid depletion of oxygen was detected in the medium even when no cells were present. However, CORM-401 did not interfere with oxygen measurement and the expected inhibition of cellular respiration was observed. CORM-2 was not suitable for use in oxygen measurements with the extracellular flux technology and CORM-3 application did not show any effect in this system. However, CO-dependent inhibition of cellular respiration was observed with CORM-401. Based on the present experiments it is concluded, that CORM-401 produced most reliable CO-specific results for the modulation of typical CO targets. For studies on CO-dependent biological effects on intracellular heme groups, CORM-2 and CORM-3 were less suitable. Depending on the experimental setting, data achieved with these compounds should be evaluated with caution., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The rotational spectrum of 2-methylthiazole was recorded using two pulsed molecular jet Fourier transform microwave spectrometers operating in the frequency range of 2-40 GHz. Due to the internal rotation of the methyl group, all rotational transitions were split into A and E symmetry species lines, which were analyzed using the programs XIAM and BELGI-C s -hyperfine, yielding a methyl torsional barrier of 34.796 75(18) cm -1 . This value was compared with that found in other monomethyl substituted aromatic five-membered rings. The 14 N quadrupole coupling constants were accurately determined to be χ aa = 0.5166(20) MHz, χ bb - χ cc = -5.2968(50) MHz, and χ ab = -2.297(10) MHz by fitting 531 hyperfine components. The experimental results were supplemented by quantum chemical calculations.

The microwave spectrum of heptan-2-one (CH 3 COC 4 H 8 CH 3 ) was recorded in the frequency range from 2 to 40 GHz using two molecular jet Fourier transform microwave spectrometers. The two energetically most favorable conformers could be identified and fitted with standard deviations close to measurement accuracy. The splittings arising from the internal rotations of two methyl groups, the acetyl methyl group CH 3 CO- and the pentyl methyl group -C 4 H 8 CH 3 , could be resolved. The barriers to internal rotation of the acetyl methyl group are 185.666(14) and 233.418(32) cm -1 for conformer I and II, respectively, and can be linked to their specific geometries. For the pentyl methyl group, the respective barrier heights are 982.22(86) and 979.2(21) cm -1 .

Cerium (Ce) oxide nanoparticles (CNP; nanoceria) are reported to have cytotoxic effects on certain cancerous cell lines, while at the same concentration they show no cytotoxicity on normal (healthy) cells. Redox-active CNP exhibit both selective prooxidative as well as antioxidative properties. The former is proposed to be responsible for impairment of tumor growth and invasion and the latter for rescuing normal cells from reactive oxygen species (ROS)-induced damage. Here we address possible underlying mechanisms of prooxidative effects of CNP in a metastatic human melanoma cell line. Malignant melanoma is the most aggressive form of skin cancer, and once it becomes metastatic the prognosis is very poor. We have shown earlier that CNP selectively kill A375 melanoma cells by increasing intracellular ROS levels, whose basic amount is significantly higher than in the normal (healthy) counterpart, the melanocytes. Here we show that CNP initiate a mitochondrial increase of ROS levels accompanied by an increase in mitochondrial thiol oxidation. Furthermore, we observed CNP-induced changes in mitochondrial bioenergetics, dynamics, and cristae morphology demonstrating mitochondrial dysfunction which finally led to tumor cell death. CNP-induced cell death is abolished by administration of PEG-conjugated catalase. Overall, we propose that cerium oxide nanoparticles mediate cell death via hydrogen peroxide production linked to mitochondrial dysfunction., Competing Interests: The authors have declared that no competing interests exist.

To accurately characterize the large amplitude motions and soft degrees of freedom of isolated molecules, sampling their conformational landscape by molecular mechanics and quantum chemical calculations may provide a valuable insight into the structure and dynamics. However, the resulting models need to be validated by a reliable experimental counterpart. For ethyl pentanoates, which belong to the family of fruit esters, benchmark calculations at different levels of theory showed that the C-C bond in proximity to the ester carbonyl group exhibits a large amplitude motion that is extremely sensitive to the choice of quantum chemical method and basis set. In such cases, insights from high-resolution molecular jet techniques are ideal to accurately identify and characterize soft degrees of freedom. Here, we report on the most abundant conformer of ethyl 2-ethyl butyrate using Fourier-transform microwave spectroscopy. We show that - unlike other structurally related pentanoates for which gas-phase and crystallographic data is available - ethyl 2-ethyl butyrate possesses a C s symmetry plane under molecular jet conditions., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mitochondria are important (patho)physiological sources of reactive oxygen species (ROS) that mediate mitochondrial dysfunction and phospholipid oxidation; an increase in mitochondrial content of oxidized phospholipid (OxPL) associates with cell death. Previously we showed that the circulating OxPL 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) increases in patients with Alzheimer's disease (AD), and associates with lower plasma antioxidant oxocarotenoids, zeaxanthin, and lutein. Since oxocarotenoids are metabolized in mitochondria, we propose that during AD, lower concentrations of mitochondrial zeaxanthin and lutein may result in greater phospholipid oxidation and predispose to neurodegeneration. Here, we have investigated whether non-toxic POVPC concentrations impair mitochondrial metabolism in differentiated (d)SH-SY5Y neuronal cells and whether there is any protective role for oxocarotenoids against mitochondrial dysfunction. After 24 hours, glutathione (GSH) concentration was lower in neuronal cells exposed to POVPC (1-20 μM) compared with vehicle control without loss of viability compared to control. However, mitochondrial ROS production (determined by MitoSOX oxidation) was increased by 50% only after 20 μM POVPC. Following delivery of lutein (0.1-1 μM) and zeaxanthin (0.5-5 μM) over 24 hours in vitro, oxocarotenoid recovery from dSH-SY5Y cells was > 50%. Co-incubation with oxocarotenoids prevented loss of GSH after 1 μM but not 20 μM POVPC, whereas the increase in ROS production induced by 20 μM POVPC was prevented by lutein and zeaxanthin. Mitochondrial uncoupling increases and ATP production is inhibited by 20 μM but not 1 μM POVPC; carotenoids protected against uncoupling although did not restore ATP production. In summary, 20 μM POVPC induced loss of GSH and a mitochondrial bioenergetic deficit in neuronal cells that was not mitigated by oxocarotenoids.

Malignant melanoma is an aggressive type of cancer and the deadliest form of skin cancer. Even though enormous efforts have been undertaken, in particular the treatment options against the metastasizing form are challenging and the prognosis is generally poor. A novel therapeutical approach is the application of secondary plant constituents occurring in food and food products. Herein, the effect of the dietary chalcone cardamonin, inter alia found in Alpinia species, was tested using human malignant melanoma cells. These data were compared to cardamonin treated normal melanocytes and dermal fibroblasts representing healthy cells. To investigate the impact of cardamonin on tumor and normal cells, it was added to monolayer cell cultures and cytotoxicity, proliferation, tumor invasion, and apoptosis were studied with appropriate cell biological and biochemical methods. Cardamonin treatment resulted in an apoptosis-mediated increase in cytotoxicity towards tumor cells, a decrease in their proliferation rate, and a lowered invasive capacity, whereas the viability of melanocytes and fibroblasts was hardly affected at such concentrations. A selective cytotoxic effect of cardamonin on melanoma cells compared to normal (healthy) cells was shown in vitro. This study along with others highlights that dietary chalcones may be a valuable tool in anticancer therapies which has to be proven in the future in vivo., Competing Interests: The authors have declared that no competing interests exist.

Low barriers to internal rotations are especially challenging for both the experimental and theoretical determinations because they result in large tunneling splittings which are hard to assign and in potential functions that can be difficult to model. In the present work, the internal rotations of two methyl groups of 2,4-dimethylanisole were analyzed and modeled using a newly developed computer code, called ntop, adapted for fitting the high-resolution torsion-rotation spectra of molecules with two or more methyl rotors. The spectrum was measured using a pulsed molecular jet Fourier transform microwave spectrometer operating in the frequency range of 2.0-26.5 GHz, revealing internal rotation tunneling quintets with splittings of up to several gigahertz. The V 3 potential barriers are 441.139(23) cm -1 and 47.649(30) cm -1 for the o- and p-methyl groups, respectively. Quantum chemical calculations predicted only one conformer with the methoxy group in the anti position related to the neighboring o-methyl group. While the results from geometry optimizations were reliable, ab initio calculations at the MP2 level did not reproduce the low torsional barriers, calling for further experiments on related systems and additional theoretical models.

Next to its well-studied toxicity, carbon monoxide (CO) is recognized as a signalling molecule in various cellular processes. Thus, CO-releasing molecules (CORMs) are of considerable interest for basic research and drug development. Aim of the present study was to investigate if CO, released from CORMs, inhibits cytochrome P450-dependent monooxygenase (CYP) activity and modulates xenobiotic metabolism. CORM-401 was used as a model CO delivering compound; inactive CORM-401 (iCORM-401), unable to release CO, served as control compound. CO release from CORM-401, but not from iCORM-401, was validated using the cell free myoglobin assay. CO-dependent inhibition of CYP activity was shown by 7-ethoxyresorufin-O-deethylation (EROD) with recombinant CYP and HepG2 cells. Upon CORM-401 exposure EROD activity of recombinant CYP decreased concentration dependently, while iCORM-401 had no effect. Treatment with CORM-401 decreased EROD activity in HepG2 cells at concentrations higher than 50 μM CORM-401, while iCORM-401 showed no effect. At the given concentrations cell viability was not affected. Amitriptyline was selected as a model xenobiotic and formation of its metabolite nortriptyline by recombinant CYP was determined by HPLC. CORM-401 treatment inhibited the formation of nortriptyline whereas iCORM-401 treatment did not. Overall, we demonstrate CO-mediated inhibitory effects on CYP activity when applying CORMs. Since CORMs are currently under drug development, the findings emphasize the importance to take into account that this class of compounds may interfere with xenobiotic metabolism., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Using two molecular jet Fourier transform spectrometers, the microwave spectrum of hexan-2-one, also called methyl n-butyl ketone, was recorded in the frequency range from 2 to 40 GHz. Three conformers were assigned and fine splittings caused by the internal rotations of the two terminal methyl groups were analyzed. For the acetyl methyl group CH 3 COC 3 H 6 CH 3 , the torsional barrier is 186.9198(50) cm -1 , 233.5913(97) cm -1 , and 182.2481(25) cm -1 for the three observed conformers, respectively. The value of this parameter could be linked to the structure of the individual conformer, which enabled us to create a rule for predicting the barrier height of the acetyl methyl torsion in ketones. The very small splittings arising from the internal rotation of the butyl methyl group CH 3 COC 3 H 6 CH 3 could be resolved as well, yielding the respective torsional barriers of 979.99(88) cm -1 , 1016.30(77) cm -1 , and 961.9(32) cm -1 ., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hierarchically assembled helicates consisting of lithium-bridged triscatecholate titanium(iv) complexes represent a powerful self-assembled supramolecular system with applications as e.g. molecular balances for the evaluation of weak interactions, stereoselectivity switches in asymmetric synthesis or molecular switches. Their applications or properties are based on the monomer-dimer equilibrium which can be easily observed in solution. The dimer is the only species in the crystal. After dissolution, the dimer slowly dissociates into the monomer until the equilibrium is reached. This can be observed by NMR spectroscopy to investigate the kinetics of the dissociation process. A strong steric effect can be observed by studying differently substituted ligands. Activation energies of the dissociation process can be correlated with the size of the ester substituents and the system may be described as a molecular buckle.

The microwave spectrum of 3,4-dimethylanisole, a molecule containing three methyl groups allowing for internal rotation, was recorded using a pulsed molecular jet Fourier transform microwave spectrometer operating in the frequency range from 2.0 to 26.5 GHz. Quantum chemical calculations yielded two conformers with an  anti and a syn configuration of the methoxy group, both of which were assigned in the experimental spectrum. Torsional splittings due to the internal rotations of two methyl groups attached to the aromatic ring were resolved and analyzed. The rotational-torsional transitions could be reproduced to measurement accuracy, yielding well-determined rotational and internal rotation parameters. The torsional barriers of the methyl groups at the meta and para position were deduced to be 430.00(37) and 467.90(17) cm -1 , respectively, for the syn-conformer. The respective values for the anti-conformer are 499.64(26) and 533.54(22) cm -1 . A labeling scheme for the G 18 group written as the semidirect product ( C 3 I ⊗ C 3 I ) (× C s was introduced.

Age-associated cognitive impairment in general and dementia in particular are a global concern. Preventive lifestyle strategies are highly used but there is a lack of information on the reciprocal relationships between nutrition biomarkers and measures of both cognitive and physical performance. To fill this gap of knowledge, the relationship between plasma levels of the robust nutrition- and antioxidant defense-related biomarkers carotenoid and tocopherols and both indicators of cognitive and physical performance was investigated in a group of persons with mild cognitive impairment participating in the NeuroExercise Study at the German Sport University in Cologne, Germany. In 56 participants with full dataset, significant correlations independently of fruit and vegetable intake were found between plasma levels of β-cryptoxanthin and Timed Up&Go test ( p < 0.05), γ-tocopherol and number of daily steps ( p < 0.01), as well as between four out of six measured carotenoids-lutein; zeaxanthin; β-cryptoxanthin and β-carotene-and the computerized CogState International Shopping List subtest ( p < 0.01). In light of the increasing attention towards the nutritional cognitive neuroscience of carotenoids, computerized measures of cognitive performance might be further implemented in future studies investigating the effects of lifestyle interventions against cognitive and physical impairment.

The microwave spectrum of 4-hexyn-3-ol, CH 3 -C≡C-CH(OH)-CH 2 CH 3 , was recorded in the frequency range of 2-26.5 GHz by molecular jet Fourier transform microwave spectroscopy. The conformational analysis based on quantum chemical calculations yielded nine conformers exhibiting C 1 symmetry, of which three could be assigned in the experimental spectrum. The propynyl methyl group CH 3 -C≡C- experiences internal rotation with a very low barrier due to the presence of the cylindrically symmetric -C≡C- group serving as a spacer to the rest of the molecule, which is 7.161 012(7) cm -1 , 4.236 5(26) cm -1 , and 7.901 6(39) cm -1 for the three assigned conformers, respectively. The spectrum was analyzed with the program XIAM using the combined axis method and the program BELGI-C 1 using the rho axis method and a very flexible Hamiltonian which yields fits with root-mean-square deviations within the measurement accuracy.

Background & Aims: Surgical trauma leads to an inflammatory response that causes surgical morbidity. Reduced antioxidant micronutrient (AM) a levels and/or excessive levels of Reactive Oxygen Species (ROS) b have previously been linked to delayed wound healing and presence of chronic wounds. We aimed to evaluate the effect of pre-operative supplementation with encapsulated fruit and vegetable juice powder concentrate (JuicePlus+ ® ) on postoperative morbidity and Quality of Life (QoL) c ., Methods: We conducted a randomised, double-blind, placebo-controlled two-arm parallel clinical trial evaluating postoperative morbidity following lower third molar surgery. Patients aged between 18 and 65 years were randomised to take verum or placebo for 10 weeks prior to surgery and during the first postoperative week. The primary endpoint was the between-group difference in QoL over the first postoperative week, with secondary endpoints being related to other measures of postoperative morbidity (pain and trismus)., Results: One-hundred and eighty-three out of 238 randomised patients received surgery (Intention-To-Treat population). Postoperative QoL tended to be higher in the active compared to the placebo group. Furthermore, reduction in mouth opening 2 days after surgery was 3.1 mm smaller (95% CI 0.1, 6.1), the mean pain score over the postoperative week was 8.5 mm lower (95% CI 1.8, 15.2) and patients were less likely to experience moderate to severe pain on postoperative day 2 (RR 0.58, 95% CI 0.35, 0.95), comparing verum to placebo groups., Conclusion: Pre-operative supplementation with a fruit and vegetable supplement rich in AM may improve postoperative QoL and reduce surgical morbidity and post-operative complications after surgery., Trial Registration: ClinicalTrials.gov Identifier: NCT01145820; Registered June 16, 2010., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

BH3 mimetics, such as BH3I-1, act as Bcl-2 antagonists, promote apoptosis and are used in basic research studies on apoptotic signaling and are currently tested as experimental anti-tumor agents. The present study addresses time- and dose-dependent responses of BH3I-1 on apoptosis, cellular stress defense mediated by heme oxygenase-1 (HO-1), and mitochondrial morphology. As expected, treatment of normal human dermal fibroblasts with BH3I-1 induced apoptosis as determined by typical markers including cytochrome c release, loss of procaspase-3, and PARP cleavage. Induction of the cellular stress response marker HO-1 precedes apoptosis induction whereas fragmentation of the mitochondrial network was triggered even more rapidly. No difference in apoptosis induction was found upon depletion of HO-1 by siRNA compared to controls suggesting that apoptosis induction by BH3I-1 is not affected by HO-1. To evaluate the functional interplay between mitochondrial fragmentation and HO-1 induction, murine embryonic fibroblasts lacking the fission factor Drp1 were used. In Drp1 knock out cells, HO-1 levels were low compared to wild type cells, both in untreated controls as well as after BH3I-1 exposure, demonstrating that Drp1 is at least in part required for determining basal and inducible HO-1 levels. Considering the sequence of events, it was shown here that BH3I-1 dependent apoptosis is a rather late event, while effects on mitochondrial morphology and cellular stress response (HO-1 induction) are observed rapidly after exposure of cells to the compound. We propose that BH3I-1 is a valuable tool for studying cellular stress responses as well as mitochondrial dynamics in future studies. Since BH3 mimetics are promising experimental anticancer drugs, our data further imply that additional biological effects such as upregulation of detoxifying systems or changes in mitochondrial dynamics could interfere, in combination therapy, with selective drug toxicity and thus need to be taken into account for drug development., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The rotational spectra of two conformers of pentan-2-one (also known as methyl propyl ketone) were recorded in the frequency range from 2 to 40 GHz using two molecular jet Fourier transform microwave spectrometers. Fine splittings due to the internal rotations of the acetyl methyl group CH 3 CO- and the butyryl methyl group -COCH 2 CH 2 CH 3 were resolved and analyzed with high accuracy. The torsional barriers of the acetyl and the butyryl methyl groups are 238.14 and 979 cm -1 , respectively, for the lowest energy conformer, as well as 188.384 and 1032 cm -1 , respectively, for the other one. From the results obtained for the acetyl methyl group, a general rule to predict its torsional barrier in ketones based on the molecular symmetry is proposed.

To determine the structural properties of 2,3-dimethylanisole, a multidisciplinary approach was carried out where gas phase rotational spectroscopy recording a spectrum from 2 to 26.5 GHz using a pulsed molecular jet Fourier transform microwave spectrometer was combined with solid-state X-ray diffraction. Both methods revealed that only one conformer with a planar heavy-atom structure exists. In the solid state, the packing in the monoclinic space group is P2 1 /n with Z=4. In the gas phase spectrum, torsional splittings due to the internal rotations of two methyl groups attached to the phenyl ring were resolved and analyzed, providing an estimate of the barriers to methyl internal rotation of V 3 =26.9047(5) and 518.7(12) cm -1 for the methyl groups at the ortho- and meta-position, respectively. The coupling between the two internal rotations is modeled on a two-dimensional potential energy surface, which was obtained by quantum chemical calculations at the B3LYP/6-311++G(d,p) level of theory., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

During exercise in hypoxia, O 2 delivery to brain and muscle is compromised, and oxidative stress is elicited. Cocoa flavanols (CF) have antioxidant capacities and can increase blood flow by stimulating endothelial function. We aimed to examine the effects of 7-day CF intake on oxidative stress, nitric oxide production, and tissue oxygenation in response to exercise in normobaric hypoxia (14.3% O 2 ). In a randomized, double-blind, cross-over study, 14 well-trained male cyclists completed four trials: exercise in normoxia or hypoxia, after 7-day CF or placebo intake. Flow-mediated dilation (FMD) was measured before intake of the last dose CF or placebo. One hundred minutes later, 20-min steady-state (SS; 45% V̇o 2max ) and 20-min time trial (TT) (cycling) were performed. Blood samples were taken. Prefrontal and muscular oxygenation was assessed by near-infrared spectroscopy. At baseline, FMD was increased by CF. Hypoxia increased exercise-induced elevations in lipid peroxidation and antioxidant capacity. CF suppressed exercise-induced lipid peroxidation but did not influence antioxidant capacity. At rest and during SS, prefrontal and muscular oxygenation was decreased by hypoxia. CF elevated prefrontal oxygenation but did not impact muscular oxygenation. During TT, hypoxia accelerated the exercise-induced decrease in prefrontal oxygenation, but not in muscular oxygenation. During TT, CF did not alter prefrontal and muscular oxygenation. CF did not change plasma nitrite, nitrate, and arginine:citrulline. During high-intensity exercise, CF improved neither tissue oxygenation nor performance in well-trained athletes. At rest and during moderate-intensity exercise, CF reduced exercise-induced lipid peroxidation and partially restored the hypoxia-induced decline in prefrontal oxygenation. NEW & NOTEWORTHY For the first time, we showed that CF had beneficial effects on endothelial function at rest, as well as on prefrontal oxygenation at rest and during moderate-intensity exercise, both in normoxia and hypoxia. Moreover, we showed that CF intake inhibited oxidative stress during exhaustive exercise in hypoxia.

The microwave spectrum of m-methylanisole (also known as 3-methylanisole, or 3-methoxytoluene) was measured using a pulsed molecular jet Fourier transform microwave spectrometer operating in the frequency range of 2-26.5 GHz. Quantum chemical calculations predicted two conformers with the methoxy group in trans or cis position related to the ring methyl group, both of which were assigned in the experimental spectrum. Due to the internal rotation of the ring methyl group, all rotational transitions introduced large A-E splittings up to several GHz, which were analyzed with a newly developed program, called aixPAM, working in the principal axis system. There are significant differences in the V 3 potential barriers of 55.7693(90) cm -1 and 36.6342(84) cm -1 determined by fitting 223 and 320 torsional components of the cis and the trans conformer, respectively. These values were compared with those found in other m-substituted toluenes as well as in o- and p-methylanisole. A comparison between the aixPAM and the XIAM code (using a combined axis system) was also performed.

Purpose: Polymeric drugs, including patiromer (Veltassa®), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administered drugs during transit of the gastrointestinal tract remains. Here we elucidate the properties correlated with drug-patiromer binding using quantitative structure-property relationship (QSPR) models., Methods: We selected 28 drugs to evaluate for binding to patiromer in vitro over a range of pH and ionic conditions intended to mimic the gut environment. Using this in vitro data, we developed QSPR models using step-wise linear regression and analyzed over 100 physiochemical drug descriptors., Results: Four descriptors emerged that account for ~70% of patiromer-drug binding in vitro: the computed surface area of hydrogen bond accepting atoms, ionization potential, electron affinity, and lipophilicity (R 2  = 0.7, Q 2  = 0.6). Further, certain molecular properties are shared by nonbinding, weak, or strong binding compounds., Conclusions: These findings offer insight into drivers of in vitro binding to patiromer and describe a useful approach for assessing potential drug-binding risk of investigational polymeric drugs.

The biomedical application of cerium oxide nanoparticles (nanoceria) is a focal point of research for a few years. The biochemical effects of nanoceria depend on various factors including particle size, oxidation state of cerium, oxygen vacancies on the surface, use of dispersants or coatings, pH and cell type. Due to their autocatalytic redox-activity, these particles are considered to act as a specific anti-cancer tool with less side effects on healthy cells and tissues, as the particles kill tumor cells, while protecting healthy cells from oxidative damage. In the present study, four different types of nanoceria were investigated with regard to their impact on biochemical parameters in vitro, which play a pivotal role in tumor-stroma interaction. The obtained data and presented in vitro test parameters will be helpful in designing nanoceria compositions, which are ideally suited for anticancer therapy, either as a 'stand alone drug' or in combination with other chemotherapeutics.

We report on the molecular structures of the two most abundant conformers of n-octanal observed by molecular beam Fourier transform microwave spectroscopy. Next to limonene, which is the main component of citrus-oil, octanal and other n-alkyl aldehydes strongly enhance the typical fresh smell of lemon-oil. Due to the high flexibility of its n-alkyl chain and the high number of possible conformers, different semi-empirical methods (AM1, PM3, MMFF94) were used to sample the conformational space of octanal before performing more sophisticated quantum chemical calculations at the MP2 level of theory. This technique has previously been shown to be an ideal tool to characterize relevant odorant structures in fragrance chemistry. The structure of octanal and structurally related molecules is discussed in the context of the most abundant chain conformations and the potential use of the microwave validated structures for further studies in biological media., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Cocoa flavanols (CF) can stimulate vasodilation by improved nitric oxide (NO) synthesis and have antioxidant and anti-inflammatory capacities. This study aimed to examine whether acute CF intake can affect exercise-induced changes in antioxidant capacity, oxidative stress, inflammation and NO production, as well as exercise performance and recovery in well-trained cyclists ., Methods: Twelve well-trained male cyclists (mean ± SD age, VO2max: 30 ± 3 years, 63.0 ± 3.5 ml/kg/min) participated in this randomized, double-blind, cross over study. On 2 separate occasions, subjects performed two 30-min time trials 1.5 (TT1) and 3 (TT2) hours after CF (900 mg CF) or placebo (PL, 13 mg CF) intake, interposed by passive rest. Lactate, glucose, heartrate, rating of perceived exertion (RPE) and power output were measured during the TTs. Blood was drawn at baseline, before and after each TT and analyzed for epicatechin serum concentrations, trolox equivalent antioxidative capacity (TEAC), uric acid (UA), malonaldehyde (MDA), L-arginine/ADMA, citrulline, interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α plasma concentrations. Relative changes in blood markers and pacing strategy during TT were analysed by repeated measured ANOVA. TT performance was compared between PL and CF by paired t-test., Results: Epicatechin concentrations were increased by CF intake. Exercise-induced increase in TEAC/UA was improved by CF intake (F(1) = 5.57; p  = .038) (post-TT1: PL: 113.34 ± 3.9%, CF: 117.64 ± 3.96%, post-TT2: PL: 108.59 ± 3.95%, CF: 123.72 ± 7.4% to baseline), while exercise-induced increases in MDA, IL-1 and IL-6 were not affected by CF intake. TNF-α was unaltered by exercise and by CF. Exercise-induced decreases in L-arginine/ADMA and increases in citrulline were not affected by CF intake. TT1 and TT2 performance and exercise-induced physiological changes were unaffected by CF intake., Conclusion: Acute CF intake increased total antioxidant capacity in rest and during exercise, but did not affect exercise-induced lipid peroxidation, inflammation, nor NO production in healthy athletes. Acute CF intake did not improve TT performance and recovery., Trial Registration: ISRCTN32875, 21-11-2016, retrospectively registered.

The microwave spectrum of o-methyl anisole (2-methoxytoluene), CH 3 OC 6 H 4 CH 3, has been measured by using a pulsed molecular jet Fourier transform microwave spectrometer operating in the frequency range 2-26.5 GHz. Conformational analysis using quantum chemical calculations at the MP2/6-311++G(d,p) level of theory yields only one stable conformer with a C s structure, which was assigned in the experimental spectrum. A-E splittings due to the internal rotation of the ring methyl group could be resolved and the barrier to internal rotation was determined to be 444.05(41) cm -1 . The experimentally deduced molecular parameters such as rotational and centrifugal distortion constants as well as the torsional barrier of the ring methyl group are in agreement with the calculated values., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)