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Load-independent myocardial contractility was strongly decreased in mActin-Tg mice while total peripheral vascular resistance (TPR) was significantly increased. As compared to vehicle-treated animals, a 3-week treatment with [Pyr1]apelin-13 significantly improved EF%, SV, E/A, DT and corrected TPR, with no significant effect on load-independent indices of myocardial contractility, blood pressure and heart rate. In conclusion [Pyr1]apelin-13 displayed no intrinsic contractile effect but improved cardiac function in dilated cardiomyopathy mainly by reducing peripheral vascular resistance, with no change in blood pressure.Recently, there has been an increased demand for functional foods, to reduce the risk of age-related cognitive impairment, dementia, and Alzheimer's disease. Among them, plant-derived bioactive compounds, such as phytochemicals and peptides, have notable potential in improving memory and cognitive functions. Many studies have provided potential data concerning the characteristics and structure-activity relationships of memory-enhancing peptides. 1-Thioglycerol When considering the proof of efficacy of these plant-based peptides in humans as neurological treatment options, it is necessary to accumulate evidence concerning their bioavailability and permeability through blood-brain barrier (BBB). This review focuses on the memory-enhancing effects of peptides derived from plant proteins and presents a current perspective on their structure-activity relationships and BBB permeability.
P-glycoprotein (P-gp) is a prevalent resistance mediator and it requires considerable cellular energy to ensure ATP dependent efflux of anticancer drugs. The glycolytic pathway generates the majority of catabolic energy in cancer cells; however, the high rates of P-gp activity places added strain on its inherently limited capacity to generate ATP. This is particularly relevant for compounds such as verapamil that are believed to trap P-gp in a futile transport process that requires continuing ATP consumption. Ultimately, this leads to cell death and the hypersensitivity of resistant cells to verapamil is termed collateral sensitivity.

We show that the addition of verapamil to resistant cells produces a prominent reduction in ATP levels that supports the idea of disrupted energy homeostasis. Even in the absence of verapamil, P-gp expressing cells display near maximal rates of glycolysis and oxidative phosphorylation, which prevents an adequate response to the demand for ATP to sustain transport activity. Moreover, the near perpetually maximal rate of oxidative phosphorylation in the presence of verapamil resulted in elevated levels of reactive oxygen species that affect cell survival and underscore collateral sensitivity.

Our results demonstrate that the strained metabolic profiles of P-gp expressing resistant cancer cells can be overwhelmed by additional ATP demands.

Consequently, collateral sensitising drugs may overcome the resistant phenotype by exploiting, rather than inhibiting, the energy demanding activity of pumps such as P-gp.
Consequently, collateral sensitising drugs may overcome the resistant phenotype by exploiting, rather than inhibiting, the energy demanding activity of pumps such as P-gp.
Recently, through comprehensive medicinal chemistry efforts, we have found a new daptomycin analogue, termed kynomycin, showing enhanced activity against both methicillin-resistant S. aureus and vancomycin-resistant Enterococcus in vitro and in vivo, with improved pharmacokinetics and lower cytotoxicity than daptomycin.

In this study we compared the physicochemical properties of kynomycin with those of daptomycin from an atomic perspective by using Nuclear Magnetic Resonance spectroscopy and Molecular Dynamics simulations.

We observed that kynurenine methylation changes daptomycin's key physicochemical properties; its calcium dependent oligomerization efficiency is improved and the modified kynurenine strengths contacts with the lipid tail and tryptophan residues. In addition, it is observed that, compared to daptomycin, kynomycin tetramer is more stable and binds stronger to calcium. The combined experiments provide key clues for the improved antibacterial activity of kynomycin.

We expect that this approach will help study the calcium binding and oligomerization features of new calcium dependent peptide antibiotics.
We expect that this approach will help study the calcium binding and oligomerization features of new calcium dependent peptide antibiotics.
Restriction endonucleases belong to prokaryotic restriction-modification systems, that protect host cells from invading DNA. Type II restriction endonucleases recognize short 4-8bp sequences in the target DNA and cut both DNA strands producing double strand breaks. Type II restriction endonuclease Kpn2I cleaves 5'-T/CCGGA DNA sequence ("/" marks the cleavage position). Analysis of protein sequences suggested that Kpn2I belongs to the CCGG-family, which contains ten enzymes that recognize diverse nucleotides outside the conserved 5'-CCGG core and share similar motifs for the 5'-CCGG recognition and cleavage.

We solved a crystal structure of Kpn2I in a DNA-free form at 2.88Å resolution. From the crystal structure we predicted active center and DNA recognition residues and tested them by mutational analysis. We estimated oligomeric state of Kpn2I by SEC-MALS and performed plasmid DNA cleavage assay to elucidate DNA cleavage mechanism.

Structure comparison confirmed that Kpn2I shares a conserved active site and structural determinants for the 5'-CCGG tetranucleotide recognition with other restriction endonucleases of the CCGG-family. Guided by structural similarity between Kpn2I and the CCGG-family restriction endonucleases PfoI and AgeI, Kpn2I residues involved in the outer base pair recognition were proposed.

Kpn2I is an orthodox Type IIP restriction endonuclease, which acts as a dimer. Kpn2I shares structural similarity to the CCGG-family restriction endonucleases PfoI, AgeI and PspGI.

The Kpn2I structure concluded the studies of the CCGG-family, covering detailed structural and biochemical characterization of eleven restriction enzymes and their complexes with DNA.
The Kpn2I structure concluded the studies of the CCGG-family, covering detailed structural and biochemical characterization of eleven restriction enzymes and their complexes with DNA.Marine microorganisms have been a resource for novel therapeutic drugs for decades. In addition to anticancer drugs, the drug acyclovir, derived from a marine sponge, is FDA-approved for the treatment of human herpes simplex virus-1 infections. Most alphaviruses that are infectious to terrestrial animals and humans, such as Venezuelan and eastern equine encephalitis viruses (VEEV and EEEV), lack efficient antiviral drugs and it is imperative to develop these remedies. To push the discovery and development of anti-alphavirus compounds forward, this study aimed to isolate and screen for potential antiviral compounds from cultured marine microbes originating from the marine environment. Compounds from marine microbes were of interest as they are prolific producers of bioactive compounds across the spectrum of human diseases and infections. Homoseongomycin, an actinobacteria isolated from a marine sponge displayed impressive activity against VEEV from a total of 76 marine bioactive products. The 50% effective concentration (EC50) for homoseongomycin was 8.6 μM for suppressing VEEV TC-83 luciferase reporter virus replication. Homoseongomycin was non-toxic up to 50 μM and partially rescued cells from VEEV induced cell death. Homoseongomycin exhibited highly efficient antiviral activity with a reduction of VEEV infectious titers by 8 log10 at 50 μM. It also inhibited EEEV replication with an EC50 of 1.2 μM. Mechanism of action studies suggest that homoseongomycin affects both early and late stages of the viral life cycle. Cells treated with 25 μM of homoseongomycin had a ~90% reduction in viral entry. In comparison, later stages showed a more robust reduction in infectious titers (6 log10) and VEEV extracellular viral RNA levels (4 log10), but a lesser impact on intracellular viral RNA levels (1.5 log10). In sum, this work demonstrates that homoseongomycin is a potential anti-VEEV and anti-EEEV compound due to its low cytotoxicity and potent antiviral activity.There are well known phenotypic differences in sweet-liking across individuals, but it remains unknown whether these are related to broader underlying differences in interoceptive abilities (abilities to sense the internal state of the body). Here, healthy women (N = 64) classified as sweet likers (SLs) or sweet dislikers (SDs) completed a bimodal interoception protocol. A heartbeat tracking and a heartbeat discrimination task determined cardiac interoception; both were accompanied by confidence ratings. A water load task, where participants consumed water to satiation and then to maximum fullness was used to assess gastric interoceptive abilities. Motivational state, psychometric characteristics and eating behaviour were also assessed. SLs performed significantly better than SDs on both heartbeat tasks, independently of impulsivity, anxiety, depression, and alexithymia. No differences in metacognitive awareness and subjective interoceptive measures were found. With gastric interoception, SLs were more sensitive to stomach distention, and they ingested less water than SDs to reach satiety when accounting for stomach capacity. SLs also scored higher on mindful and intuitive eating scales and on emotional eating particularly in response to negative stimuli; emotional overeating was fully mediated via interoceptive performance. Overall, our data suggest the SL phenotype may reflect enhanced responsiveness to internal cues more broadly.Meat consumption is increasingly seen as unsustainable, unhealthy, and unethical. Understanding what factors help people reduce their meat intake is urgently needed. One such factor is meat disgust, a feeling reported by many vegetarians, and which could be a promising basis for meat reduction interventions. However, meat disgust and its impact on meat consumption is poorly understood. We examined meat disgust and its role in vegetarianism and reducing meat intake in a cross-sectional and longitudinal online study. We measured self-reported meat consumption, meat disgust (by self-report and Implicit Association Test), meat liking, self-control, and disgust sensitivity in N = 711 adults (57% omnivores, 28% flexitarians, 15% vegetarians) recruited from a community cohort. Results showed that 73% of vegetarians can be classified as 'meat disgusted', and that meat disgust predicted meat intake better than self-control in omnivores and flexitarians at baseline. Following up a sub-sample of participants (N = 197) after six months revealed that changes in meat intake over time were also associated with changes in meat disgust. This is the first study to quantify the impact of meat disgust on (changes in) meat consumption and its prevalence in the vegetarian and the general population. Our findings advance research into meat disgust and encourage the development of disgust-based interventions to reduce meat intake.
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