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Nature Communications Jun 2024Excitation energy transfer (EET) is a key photoinduced process in biological chromophoric assemblies. Here we investigate the factors which can drive EET into efficient...
Excitation energy transfer (EET) is a key photoinduced process in biological chromophoric assemblies. Here we investigate the factors which can drive EET into efficient ultrafast sub-ps regimes. We demonstrate how a coherent transport of electronic population could facilitate this in water solvated NADH coenzyme and uncover the role of an intermediate dark charge-transfer state. High temporal resolution ultrafast optical spectroscopy gives a 54±11 fs time constant for the EET process. Nonadiabatic quantum dynamical simulations computed through the time-evolution of multidimensional wavepackets suggest that the population transfer is mediated by photoexcited molecular vibrations due to strong coupling between the electronic states. The polar aqueous solvent environment leads to the active participation of a dark charge transfer state, accelerating the vibronically coherent EET process in favorably stacked conformers and solvent cavities. Our work demonstrates how the interplay of structural and environmental factors leads to diverse pathways for the EET process in flexible heterodimers and provides general insights relevant for coherent EET processes in stacked multichromophoric aggregates like DNA strands.
Topics: NAD; Energy Transfer; Quantum Theory; Water
PubMed: 38851775
DOI: 10.1038/s41467-024-48871-4 -
Nature Communications Jun 2024The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain...
The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.
Topics: Animals; Muscle, Skeletal; NAD; Receptors, G-Protein-Coupled; Homeostasis; Male; Glucose; Mice; Mice, Knockout; Humans; Mitochondria; Mice, Inbred C57BL; Signal Transduction; Phosphorylation
PubMed: 38851747
DOI: 10.1038/s41467-024-49100-8 -
BMC Urology Jun 2024This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development.
BACKGROUND
This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development.
METHODS
By using immunofluorescence and Western blot, we were able to locate EP receptors in the ureter. In vitro experiments assessed the impact of PGE2, receptor antagonists, and agonists on ureteral relaxation rate. We constructed a model of ureteral calculi with flowable resin and collected ureteral tissue from postoperative side of the ureter after obstruction surgery. Western blot analysis was used to determine the protein expression levels of EP receptors and the PGE2 terminal synthase mPGES-1. Additionally, PGE2 was added to smooth muscle cells to observe downstream cAMP and PKA changes.
RESULTS
The expression of EP2 and EP4 proteins in ureteral smooth muscle was verified by Western blot analysis. According to immunofluorescence, EP2 was primarily found on the cell membrane, while EP4 was found in the nucleus. In vitro, PGE2 induced concentration-dependent ureteral relaxation. Maximum diastolic rate was 70.94 ± 4.57% at a concentration of 30µM. EP2 antagonists hindered this effect, while EP4 antagonists did not. Obstructed ureters exhibited elevated mPGES-1 and EP2 protein expression (P < 0.01). Smooth muscle cells treated with PGE2 displayed increased cAMP and phosphorylated PKA.
CONCLUSIONS
PGE2 binding to EP2 induces ureteral relaxation through the cAMP-PKA pathway. This will provide a new theoretical basis for the development of new therapeutic approaches for the use of PGE2 in the treatment of ureteral stones.
Topics: Receptors, Prostaglandin E, EP2 Subtype; Cyclic AMP; Dinoprostone; Cyclic AMP-Dependent Protein Kinases; Ureteral Calculi; Animals; Ureter; Signal Transduction; Male; Muscle Relaxation
PubMed: 38851678
DOI: 10.1186/s12894-024-01504-w -
Cardiovascular Toxicology Jul 2024Antiviral therapies for treatment of COVID-19 may be associated with significant proarrhythmic potential. In the present study, the potential cardiotoxic side effects of... (Comparative Study)
Comparative Study
Antiviral therapies for treatment of COVID-19 may be associated with significant proarrhythmic potential. In the present study, the potential cardiotoxic side effects of these therapies were evaluated using a Langendorff model of the isolated rabbit heart. 51 hearts of female rabbits were retrogradely perfused, employing a Langendorff-setup. Eight catheters were placed endo- and epicardially to perform an electrophysiology study, thus obtaining cycle length-dependent action potential duration at 90% of repolarization (APD), QT intervals and dispersion of repolarization. After generating baseline data, the hearts were assigned to four groups: In group 1 (HXC), hearts were treated with 1 µM hydroxychloroquine. Thereafter, 3 µM hydroxychloroquine were infused additionally. Group 2 (HXC + AZI) was perfused with 3 µM hydroxychloroquine followed by 150 µM azithromycin. In group 3 (LOP) the hearts were perfused with 3 µM lopinavir followed by 5 µM and 10 µM lopinavir. Group 4 (REM) was perfused with 1 µM remdesivir followed by 5 µM and 10 µM remdesivir. Hydroxychloroquine- and azithromycin-based therapies have a significant proarrhythmic potential mediated by action potential prolongation and an increase in dispersion. Lopinavir and remdesivir showed overall significantly less pronounced changes in electrophysiology. In accordance with the reported bradycardic events under remdesivir, it significantly reduced the rate of the ventricular escape rhythm.
Topics: Animals; Rabbits; Female; Antiviral Agents; Isolated Heart Preparation; Action Potentials; COVID-19 Drug Treatment; Hydroxychloroquine; Arrhythmias, Cardiac; Cardiotoxicity; Alanine; Heart Rate; Adenosine Monophosphate; Heart
PubMed: 38851664
DOI: 10.1007/s12012-024-09872-3 -
Journal of Thermal Biology May 2024The objective of the study was to examine the lower limbs skin temperature (T) changes in response to exhaustive whole-body exercise in trained individuals in reference...
The objective of the study was to examine the lower limbs skin temperature (T) changes in response to exhaustive whole-body exercise in trained individuals in reference to changes in plasma adenosine triphosphate (ATP). Eighteen trained participants from distinct sport type ‒ endurance (25.2 ± 4.9 yr) and speed-power (25.8 ± 3.1 yr), and 9 controls (24,9 ± 4,3 yr) ‒ were examined. Lower limbs T and plasma ATP measures were applied in parallel in response to incremental treadmill test and during 30-min recovery period. Plasma ATP kinetics were inversely associated to changes in T. The first significant decrease in T (76-89% of V˙ O) occurred shortly before a significant plasma ATP increase (86-97% of V˙ O). During recovery, T increased, reaching pre-exercise values (before exercise vs. after 30-min recovery: 31.6 ± 0.4 °C vs. 32.0 ± 0.8 °C, p = 0.855 in endurance; 32.4 ± 0.5 °C vs. 32.9 ± 0.5 °C, p = 0.061 in speed-power; 31.9 ± 0.7 °C vs. 32.4 ± 0.8 °C, p = 0.222 in controls). Plasma ATP concentration did not returned to pre-exercise values in well trained participants (before exercise vs. after 30-min recovery: 699 ± 57 nmol l vs. 854 ± 31 nmol l, p < 0.001, η = 0.961 and 812 ± 35 nmol l vs. 975 ± 55 nmol l, p < 0.001, η = 0.974 in endurance and speed-power, respectively), unlike in controls (651 ± 40 nmol l vs. 687 ± 61 nmol·l1, p = 0.58, η = 0.918). The magnitude of T and plasma ATP response differed between the groups (p < 0.001, η = 0.410 for T; p < 0.001, η = 0.833 for plasma ATP). We conclude that lower limbs T change indirectly corresponds to the reverse course of plasma ATP during incremental exercise and the magnitude of the response depends on the level of physical activity and the associated to it long-term metabolic adaptation.
Topics: Humans; Skin Temperature; Male; Adenosine Triphosphate; Adult; Exercise; Lower Extremity; Young Adult; Female; Physical Endurance
PubMed: 38850622
DOI: 10.1016/j.jtherbio.2024.103877 -
Cephalalgia : An International Journal... Jun 2024The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers migraine attacks via cAMP, whereas the phosphodiesterase-5 inhibitor sildenafil induces migraine attacks via cGMP. Our objective was to investigate whether sildenafil could induce migraine attacks in individuals with migraine pre-treated with the CGRP-receptor antibody erenumab.
METHODS
In this randomized, double-blind, placebo-controlled, cross-over study, adults with migraine without aura received a single subcutaneous injection of 140 mg erenumab on day 1. They were then randomized to receive sildenafil 100 mg or placebo on two experimental days, each separated by at least one week, between days 8 and 21. The primary endpoint was the difference in the incidence of migraine attacks between sildenafil and placebo during the 12-h observation period after administration.
RESULTS
In total, 16 participants completed the study. Ten participants (63%) experienced a migraine attack within 12 h after sildenafil administration compared to three (19%) after placebo ( = 0.016). The median headache intensity was higher after sildenafil than after placebo (area under the curve (AUC) for the 12-h observation period, = 0.026). Furthermore, sildenafil induced a significant decrease in mean arterial blood pressure (AUC, = 0.026) and a simultaneous increase in heart rate (AUC, < 0.001) during the first hour after administration compared to placebo.
CONCLUSION
These findings provide evidence that migraine induction via the cGMP pathway can occur even under CGRP receptor blockade.
TRIAL REGISTRATION
ClinicalTrials.gov: Identifier NCT05889455.
Topics: Humans; Adult; Male; Double-Blind Method; Female; Sildenafil Citrate; Cross-Over Studies; Receptors, Calcitonin Gene-Related Peptide; Migraine Disorders; Middle Aged; Cyclic GMP; Antibodies, Monoclonal, Humanized; Calcitonin Gene-Related Peptide Receptor Antagonists; Phosphodiesterase 5 Inhibitors; Young Adult
PubMed: 38850034
DOI: 10.1177/03331024241259489 -
Scientific Reports Jun 2024Recent data indicate that extracellular ATP affects wound healing efficacy via P2Y2-dependent signaling pathway. In the current work, we propose double-modified ATP...
Recent data indicate that extracellular ATP affects wound healing efficacy via P2Y2-dependent signaling pathway. In the current work, we propose double-modified ATP analogue-alpha-thio-beta,gamma-methylene-ATP as a potential therapeutic agent for a skin regeneration. For the better understanding of structure-activity relationship, beside tested ATP analogues, the appropriate single-modified derivatives of target compound, such as alpha-thio-ATP and beta,gamma-methylene-ATP, were also tested in the context of their involvement in the activation of ATP-dependent purinergic signaling pathway via the P2Y2 receptor. The diastereomerically pure alpha-thio-modified-ATP derivatives were obtained using the oxathiaphospholane method as separate S and R diastereomers. Both the single- and double- modified ATP analogues were then tested for their impact on the viability and migration of human keratinocytes. The involvement of P2Y2-dependent purinergic signaling was analyzed in silico by molecular docking of the tested compounds to the P2Y2 receptor and experimentally by studying intracellular calcium mobilization in the human keratinocytes HaCaT. The effects obtained for ATP analogues were compared with the results for ATP as a natural P2Y2 agonist. To confirm the contribution of the P2Y2 receptor to the observed effects, the tests were also performed in the presence of the selective P2Y2 antagonist-AR-C118925XX. The ability of the alpha-thio-beta,gamma-methylene-ATP to influence cell migration was analyzed in vitro on the model HaCaT and MDA-MB-231 cells by wound healing assay and transwell migration test as well as in vivo using zebrafish system. The impact on tissue regeneration was estimated based on the regrowth rate of cut zebrafish tails. The in vitro and in vivo studies have shown that the S-alpha-thio-beta,gamma-methylene-ATP analogue promotes regeneration-related processes, making it a suitable agent for enhance wound healing. Performed studies indicated its impact on the cell migration, induction of epithelial-mesenchymal transition and intracellular calcium mobilization. The enhanced regeneration of cut zebrafish tails confirmed the pro-regenerative activity of this ATP analogue. Based on the performed studies, the S-alpha-thio-beta,gamma-methylene-ATP is proposed as a potential therapeutic agent for wound healing and skin regeneration treatment.
Topics: Wound Healing; Humans; Adenosine Triphosphate; Animals; Keratinocytes; Zebrafish; Molecular Docking Simulation; Cell Movement; Receptors, Purinergic P2Y2; Signal Transduction; Calcium; Cell Line; Cell Survival; Structure-Activity Relationship
PubMed: 38849425
DOI: 10.1038/s41598-024-63759-5 -
The Journal of Cell Biology Jul 2024How nucleocytoplasmic transport (NCT) rates change due to cellular physiology-mediated fluctuations in GTP availability remains unclear. In this issue, Scott et al....
How nucleocytoplasmic transport (NCT) rates change due to cellular physiology-mediated fluctuations in GTP availability remains unclear. In this issue, Scott et al. (https://doi.org/10.1083/jcb.202308152) demonstrate that cell migration, spreading, and nucleocytoskeletal coupling impact GTP levels, thereby regulating NCT, RNA export, and protein synthesis.
Topics: Humans; Active Transport, Cell Nucleus; Cell Movement; Cell Nucleus; Energy Metabolism; Guanosine Triphosphate; Protein Biosynthesis
PubMed: 38847483
DOI: 10.1083/jcb.202405121 -
Communications Biology Jun 2024Pericyte dysfunction, with excessive migration, hyperproliferation, and differentiation into smooth muscle-like cells contributes to vascular remodeling in Pulmonary...
Pericyte dysfunction, with excessive migration, hyperproliferation, and differentiation into smooth muscle-like cells contributes to vascular remodeling in Pulmonary Arterial Hypertension (PAH). Augmented expression and action of growth factors trigger these pathological changes. Endogenous factors opposing such alterations are barely known. Here, we examine whether and how the endothelial hormone C-type natriuretic peptide (CNP), signaling through the cyclic guanosine monophosphate (cGMP) -producing guanylyl cyclase B (GC-B) receptor, attenuates the pericyte dysfunction observed in PAH. The results demonstrate that CNP/GC-B/cGMP signaling is preserved in lung pericytes from patients with PAH and prevents their growth factor-induced proliferation, migration, and transdifferentiation. The anti-proliferative effect of CNP is mediated by cGMP-dependent protein kinase I and inhibition of the Phosphoinositide 3-kinase (PI3K)/AKT pathway, ultimately leading to the nuclear stabilization and activation of the Forkhead Box O 3 (FoxO3) transcription factor. Augmentation of the CNP/GC-B/cGMP/FoxO3 signaling pathway might be a target for novel therapeutics in the field of PAH.
Topics: Humans; Pericytes; Natriuretic Peptide, C-Type; Cyclic GMP; Signal Transduction; Forkhead Box Protein O3; Cell Proliferation; Male; Female; Pulmonary Arterial Hypertension; Middle Aged; Hypertension, Pulmonary; Adult; Receptors, Atrial Natriuretic Factor; Cells, Cultured
PubMed: 38844781
DOI: 10.1038/s42003-024-06375-3 -
Biomedical and Environmental Sciences :... May 2024Little is known about the association between whole-blood nicotinamide adenine dinucleotide (NAD ) levels and nabothian cysts. This study aimed to assess the association...
OBJECTIVE
Little is known about the association between whole-blood nicotinamide adenine dinucleotide (NAD ) levels and nabothian cysts. This study aimed to assess the association between NAD levels and nabothian cysts in healthy Chinese women.
METHODS
Multivariate logistic regression analysis was performed to analyze the association between NAD levels and nabothian cysts.
RESULTS
The mean age was 43.0 ± 11.5 years, and the mean level of NAD was 31.3 ± 5.3 μmol/L. Nabothian cysts occurred in 184 (27.7%) participants, with single and multiple cysts in 100 (15.0%) and 84 (12.6%) participants, respectively. The total nabothian cyst prevalence gradually decreased from 37.4% to 21.6% from Q1 to Q4 of NAD and the prevalence of single and multiple nabothian cysts also decreased across the NAD quartiles. As compared with the highest NAD quartile (≥ 34.4 μmol/L), the adjusted odds ratios with 95% confidence interval of the NAD Q1 was 1.89 (1.14-3.14) for total nabothian cysts. The risk of total and single nabothian cysts linearly decreased with increasing NAD levels, while the risk of multiple nabothian cysts decreased more rapidly at NAD levels of 28.0 to 35.0 μmol/L.
CONCLUSION
Low NAD levels were associated with an increased risk of total and multiple nabothian cysts.
Topics: Humans; Female; Adult; Middle Aged; NAD; Cysts; China
PubMed: 38843920
DOI: 10.3967/bes2024.052