Mecanismos compensatorios a nivel sistémico en pacientes con tronco arterial persistente / Systemic Compensatory Mechanisms in Patients with Persistent Truncus Arteriosus

Resumen Introducción: El tronco arterial persistente es una rara malformación cardíaca congénita que provoca diversas complicaciones en el sistema cardiovascular. Se caracteriza por la presencia de un tabique ventricular defectuoso, una única válvula troncal y un tronco arterial común entre la arteria pulmonar y aorta, conllevando a una mezcla entre la sangre arterial y venosa, debido a un cortocircuito cardíaco bidireccional predominante de izquierda a derecha que compromete el suministro de flujo sanguíneo, nutrientes y oxigenación sistémica. Las manifestaciones clínicas incluyen desaturación con cianosis, hipoxemia, taquicardia, taquipnea, alteraciones en la contractilidad cardíaca, pulsos distales anómalos, pérdida de peso, fatiga y hepatomegalia. Objetivo: El propósito de esta investigación es establecer hipótesis sobre los diversos mecanismos compensatorios que se activan a nivel sistémico para contrarrestar los efectos de esta malformación. Reflexión: Se sugiere que se producen respuestas biomoleculares similares en los sistemas cardiovascular, pulmonar y renal, reduciendo la producción de óxido nítrico y provocando respuestas vasoconstrictoras. A nivel hepático, se generan factores de crecimiento y se inician procesos de angiogénesis para aumentar la perfusión sanguínea. En el cerebro, se activan enzimas para incrementar el flujo sanguíneo y proporcionar oxígeno y nutrientes esenciales. Conclusión: A pesar de estos mecanismos compensatorios, no logran contrarrestar por completo las manifestaciones clínicas, conduciendo a una serie de problemas de salud, como hipertensión pulmonar, insuficiencia cardíaca, hepatomegalia, hipoperfusión de órganos y déficits neurológicos. Estos factores convergen para generar una compleja condición cardíaca que desencadena respuestas adaptativas en el cuerpo que terminan siendo una afección médica desafiante y potencialmente grave.

Abstract Introduction: Persistent truncus arteriosus is a rare congenital cardiac malformation that causes various complications in the cardiovascular system. It is characterized by the presence of a defective ventricular septum, a single truncal valve and a common truncus arteriosus between the pulmonary artery and aorta, leading to a mixture between arterial and venous blood, due to a predominantly left-to-right bidirectional cardiac shunt that compromises the supply of blood flow, nutrients, and systemic oxygenation. Clinical manifestations include desaturation with cyanosis, hypoxemia, tachycardia, tachypnea, alterations in cardiac contractility, abnormal distal pulses, weight loss, fatigue, and hepatomegaly. Aim: The purpose of this research is to establish hypotheses about the various compensatory mechanisms that are activated at a systemic level to counteract the effects of this malformation. Reflection: It is suggested that similar biomolecular responses occur in the cardiovascular, pulmonary, and renal systems, reducing nitric oxide production and causing vasoconstrictive responses. At the liver level, growth factors are generated and angiogenesis processes are initiated to increase blood perfusion. In the brain, enzymes are activated to increase blood flow and provide oxygen and essential nutrients. Conclusion: Despite these compensatory mechanisms, they fail to completely counteract the clinical manifestations, leading to a series of health problems such as pulmonary hypertension, heart failure, hepatomegaly, organ hypoperfusion, and neurological deficits. These factors converge to generate a complex cardiac condition that triggers adaptive responses in the body that end up being a challenging and potentially serious medical condition.

Differential sensitivity and specificity of Aedes aegypti and Anopheles gambiae to adenine nucleotide phagostimulants-an all-or-none response?

BACKGROUND: The decision to imbibe a blood meal is predominantly dependent on the sensitivity and specificity of haematophagous arthropods to blood-derived adenine nucleotides, in particular adenosine triphosphate (ATP). Despite previous efforts to identify and characterise the specificity and sensitivity to ATP and other adenine nucleotides, as well as the role of other blood-derived phagostimulants across the Culicidae, comparisons across species remain difficult. METHODS: The feeding response of the yellow fever mosquito Aedes aegypti and the African malaria vector Anopheles gambiae to adenine nucleotides in the presence of a carbonate buffer was assessed using a membrane feeding assay. The proportion of mosquitoes engorged and the volume imbibed by all mosquitoes was scored visually and spectrophotometrically. In addition, the proportion of prediuresing An. gambiae, as well as the volume engorged and prediuresed, was examined. RESULTS: Aedes aegypti was more sensitive to adenine nucleotides than An. gambiae, but both species maintained specificity to these phagostimulants, demonstrating a dose-dependent bimodal feeding pattern, thereby expanding our understanding of the all-or-none blood-feeding hypothesis. Feeding on the bicarbonate buffer by An. gambiae-but not that of Ae. aegypti-demonstrated a species-specific variation in how blood phagostimulants are encoded. Adenine nucleotides, with and without bovine serum albumin, were observed to dose-dependently regulate the proportion of An. gambiae prediuresing and the volumes prediuresed but not volumes engorged. CONCLUSIONS: Taken together, the results of this study expand our understanding of how mosquitoes differentially assess and respond to blood meal constituents, and provide a basis for further physiological and molecular studies.

Evaluating ATP testing for distribution system monitoring: comparison to HPC, impact of chlorine quenching, and hold time dependency.

Adenosine triphosphate (ATP) assays have a faster turnaround time and higher sensitivity than traditional cultivation methods for microbial monitoring. Challenges implementing ATP testing include incompatibility with chlorine quenching agents and hold time sensitivity, which are not well-studied. Chlorinated distribution system samples were collected from two Canadian utilities, Metro Vancouver (n = 40 samples) and Halifax Water (n = 283). No significant correlations were observed between heterotrophic cell count (HPC) and cellular ATP, suggesting these do not correlate well in waters with low biological activity (median HPC < 2 CFU/mL). However, interpretation of HPC and cATP results (based on the HPC guideline of 100 CFU/mL and cATP of 10 pg/mL) yielded the same conclusion for 95% of samples, suggesting a potential decision-making framework to replace HPC with cATP. Moreover, cATP correlates better with free chlorine (p < 0.04) compared with HPC for one of the studied systems. Importantly, adding chlorine quench (10% sodium thiosulfate) did not produce significantly different cATP results, nor did analyzing at various hold times of 4-, 6-, and 24-h. This study supports the integration of ATP testing into existing sampling procedures for water utilities, as a sensitive, fast, and reliable monitoring method.

Hyperbaric oxygen therapy in the ATLS/ACLS resuscitative management of acutely ill or severely injured patients with severe anemia: a review.

For short periods, even without the presence of red blood cells, hyperbaric oxygen can safely allow plasma to meet the oxygen delivery requirements of a human at rest. By this means, hyperbaric oxygen, in special instances, may be used as a bridge to lessen blood transfusion requirements. Hyperbaric oxygen, applied intermittently, can readily avert oxygen toxicity while meeting the body's oxygen requirements. In acute injury or illness, accumulated oxygen debt is shadowed by adenosine triphosphate debt. Hyperbaric oxygen efficiently provides superior diffusion distances of oxygen in tissue compared to those provided by breathing normobaric oxygen. Intermittent application of hyperbaric oxygen can resupply adenosine triphosphate for energy for gene expression and reparative and anti-inflammatory cellular function. This advantageous effect is termed the hyperbaric oxygen paradox. Similarly, the normobaric oxygen paradox has been used to elicit erythropoietin expression. Referfusion injury after an ischemic insult can be ameliorated by hyperbaric oxygen administration. Oxygen toxicity can be averted by short hyperbaric oxygen exposure times with air breaks during treatments and also by lengthening the time between hyperbaric oxygen sessions as the treatment advances. Hyperbaric chambers can be assembled to provide everything available to a patient in modern-day intensive care units. The complication rate of hyperbaric oxygen therapy is very low. Accordingly, hyperbaric oxygen, when safely available in hospital settings, should be considered as an adjunct for the management of critically injured or ill patients with disabling anemia.

Remdesivir triphosphate is a valid substrate to initiate synthesis of DNA primers by human PrimPol.

Remdesivir is a broad-spectrum antiviral drug which has been approved to treat COVID-19. Remdesivir is in fact a prodrug, which is metabolized in vivo into the active form remdesivir triphosphate (RTP), an analogue of adenosine triphosphate (ATP) with a cyano group substitution in the carbon 1' of the ribose (1'-CN). RTP is a substrate for RNA synthesis and can be easily incorporated by viral RNA-dependent RNA polymerases (RdRp). Importantly, once remdesivir is incorporated (now monophosphate), it will act as a delayed chain terminator, thus blocking viral RNA synthesis. It has been reported that mitochondrial Polγ is also blocked in vitro by RTP, but the low impact in vivo on mitochondrial DNA replication stalling is likely due to repriming by the human DNA-directed DNA Primase/Polymerase (HsPrimPol), which also operates in mitochondria. In this work, we have tested if RTP is a valid substrate for both DNA primase and DNA polymerase activities of HsPrimPol, and its impact in the production of mature DNA primers. RTP resulted to be an invalid substrate for elongation, but it can be used to initiate primers at the 5´site, competing with ATP. Nevertheless, RTP-initiated primers are abortive, ocassionally reaching a maximal length of 4-5 nucleotides, and do not support elongation mediated by primer/template distortions. However, considering that the concentration of ATP, the natural substrate, is much higher than the intracellular concentration of RTP, it is unlikely that HsPrimPol would use RTP for primer synthesis during a remdesivir treatment in real patients.

Betulonic Acid Inhibits Type-2 Porcine Reproductive and Respiratory Syndrome Virus Replication by Downregulating Cellular ATP Production.

Porcine reproductive and respiratory syndrome (PRRS), caused by PRRS virus (PRRSV) infection, has been a serious threat to the pork industry worldwide and continues to bring significant economic loss. Current vaccination strategies offer limited protection against PRRSV transmission, highlighting the urgent need for novel antiviral approaches. In the present study, we reported for the first time that betulonic acid (BA), a widely available pentacyclic triterpenoids throughout the plant kingdom, exhibited potent inhibition on PRRSV infections in both Marc-145 cells and primary porcine alveolar macrophages (PAMs), with IC50 values ranging from 3.3 µM to 3.7 µM against three different type-2 PRRSV strains. Mechanistically, we showed that PRRSV replication relies on energy supply from cellular ATP production, and BA inhibits PRRSV infection by reducing cellular ATP production. Our findings indicate that controlling host ATP production could be a potential strategy to combat PRRSV infections, and that BA might be a promising therapeutic agent against PRRSV epidemics.

Uridine triphosphate hybrid catalyst for carbon­carbon bond formation reactions with enhanced enantioselectivity by mercury(II) ions.

DNA hybrid catalysts are constructed by embedding active metal species into the chiral scaffolds of DNA, which have been successfully applied to some important aqueous-phase enantioselective transformations. Owing to simple components and inherent chirality, nucleotide hybrid catalysts are emerging in response to soving the unclear locations of catalytic centers and the plausible catalytic mechanisms in DNA-based asymmetric catalysis. However, the tertiary structure of nucleotides lacks tunability, severely impeding further design of nucleotide hybrid catalysts for potential applications. To this end, a design strategy for tunable nucleotide hybrid catalysts is put forward by introducing metal-mediated base pairs. Herein, we found that the formation of uracil­mercury(II)-uracil (U-Hg2+-U) base pairs could enhance the enantioselectivity in uracil-containing nucleotide-based asymmetric reactions. Compared with uracil triphosphate (UTP) complexing with Cu2+ ions (UTP∙Cu2+), the presence of Hg2+ ions gave rise to an increased enantiomeric excess (ee) of 38 % in Diels-Alder reactions and 22 % ee in Michael reactions. The Hg2+-tuning behaviors of UTP hybrid catalyst have been demonstrated to largely depend on nucleotides, Hg2+ concentrations, metal cofactors, additives and reaction types. Based on ultraviolet-visible, circular dichroism and nuclear magnetic resonance spectroscopic techniques, the chiral enhancement of Hg2+-containing UTP hybrid catalyst is proved to largely depend on the formation of U-Hg2+-U base pairs and the plausible cross-linked structure of UTP-Hg2+-UTP/Cu2+ assembly. This work provides a tunable strategy based on the concept of metal-mediated base pairs, allowing further design of potent oligonucleotide-based catalysts for other enantioselective reactions.

Pharmacology of P2X Receptors and Their Possible Therapeutic Potential in Obesity and Diabetes.

The role of P2X ionotropic receptors in the behavior of purinergic signaling on pathophysiological processes has been widely studied. In recent years, the important participation of P2X receptors in physiological and pathological processes, such as energy metabolism, characteristic inflammatory responses of the immune system, and nociceptive activity in response to pain stimuli, has been noted. Here, we explore the molecular characteristics of the P2X receptors and the use of the different agonist and antagonist agents recently described, focusing on their potential as new therapeutic targets in the treatment of diseases with emphasis on obesity, diabetes, and some of the complications derived from these pathologies.

Fusogenic Liposomes for the Intracellular Delivery of Phosphocreatine.

Background/Objective: Maintaining intracellular adenosine triphosphate (ATP) levels is essential for numerous cellular functions, including energy metabolism, muscle contraction, and nerve impulse transmission. ATP is primarily synthesized in mitochondria through oxidative phosphorylation. It is also generated in the cytosol under anaerobic conditions using phosphocreatine (PCr) as a phosphate donor to adenosine diphosphate. However, the intracellular delivery of exogenous PCr is challenging as it does not readily cross the plasma membrane. This complicates the use of PCr as a therapeutic agent to maintain energy homeostasis or to treat conditions like cerebral creatine deficiency syndrome (CDS), which results from defective creatine transporters. Methods: This study employs the use of fusogenic liposomes to deliver PCr directly into the cytosol, bypassing membrane impermeability issues. We engineered various 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-based fusogenic liposomes, incorporating phospholipids such as 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in combination with phospholipid-aromatic dye components to facilitate membrane fusion and to enhance the delivery of the PCr cargo. Liposomal formulations were co-loaded with membrane-impermeable chromophores and PCr and studied on live cells using confocal microscopy. Conclusions: We demonstrated the successful intracellular delivery of these agents and observed a 23% increase in intracellular ATP levels in cells treated with PCr-loaded liposomes. This increase was not observed with free PCr, confirming the effectiveness of the liposome-based delivery system. Additionally, cell viability assays showed minimal toxicity from the liposomes. Our results indicate that fusogenic liposomes are a promising method for the delivery of PCr (and potentially other cell-impermeable therapeutic agents) to the cellular cytosol. The approach demonstrated here could be advantageous for treating energy-related disorders and improving cellular energy homeostasis.

Adenosine Metabolism Pathway Alterations in Frontal Cortical Neurons in Schizophrenia.

Schizophrenia is a neuropsychiatric illness characterized by altered neurotransmission, in which adenosine, a modulator of glutamate and dopamine, plays a critical role that is relatively unexplored in the human brain. In the present study, postmortem human brain tissue from the anterior cingulate cortex (ACC) of individuals with schizophrenia (n = 20) and sex- and age-matched control subjects without psychiatric illness (n = 20) was obtained from the Bronx-Mount Sinai NIH Brain and Tissue Repository. Enriched populations of ACC pyramidal neurons were isolated using laser microdissection (LMD). The mRNA expression levels of six key adenosine pathway components-adenosine kinase (ADK), equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), ectonucleoside triphosphate diphosphohydrolases 1 and 3 (ENTPD1 and ENTPD3), and ecto-5'-nucleotidase (NT5E)-were quantified using real-time PCR (qPCR) in neurons from these individuals. No significant mRNA expression differences were observed between the schizophrenia and control groups (p > 0.05). However, a significant sex difference was found in ADK mRNA expression, with higher levels in male compared with female subjects (Mann-Whitney U = 86; p < 0.05), a finding significantly driven by disease (t(17) = 3.289; p < 0.05). Correlation analyses also demonstrated significant associations (n = 12) between the expression of several adenosine pathway components (p < 0.05). In our dementia severity analysis, ENTPD1 mRNA expression was significantly higher in males in the "mild" clinical dementia rating (CDR) bin compared with males in the "none" CDR bin (F(2, 13) = 5.212; p < 0.05). Lastly, antipsychotic analysis revealed no significant impact on the expression of adenosine pathway components between medicated and non-medicated schizophrenia subjects (p > 0.05). The observed sex-specific variations and inter-component correlations highlight the value of investigating sex differences in disease and contribute to the molecular basis of schizophrenia's pathology.

Optimized Method for the Synthesis of Alkyne-Modified 2'-Deoxynucleoside Triphosphates.

A general approach is presented for synthesizing alkyne-modified nucleoside triphosphates via the Sonogashira cross-coupling reaction of unprotected halogenated 2'-deoxynucleoside, followed by monophosphorylation and the reaction of the corresponding phosphoromorpholidate with tributylammonium pyrophosphate. A highly efficient approach for the milligram-scale synthesis of base-modified nucleoside triphosphates with an amino acid-like side chain was developed. The present chemical method outweighs the other reported methods of a base-modified nucleoside triphosphates synthesis in terms of it being a protection-free strategy, the shortening of reaction steps, and increased yields (about 70%). The resulting 8-alkynylated dATP was tested as a substrate for DNA polymerases in a primer extension reaction.

Evaluation of ATP bioluminescence for rapid determination of farrowing room cleanliness after pressure washing at a commercial sow farm.

Rotavirus and other pathogenic microorganisms are known to cause scours, respiratory infection, and increased mortality, spread from pig to pig via contaminated equipment, insuffcient washing, and improper disinfection processes in farrowing rooms on commercial sow farms. Pig producers have adopted cleaning procedures and biosecurity policies as an attempt to ensure farrowing rooms are free of infectious organisms before the next group of sows is introduced. Adenosine triphosphate (ATP) bioluminescence has been used in other industries to provide real-time feedback on surface cleanliness through the detection of ATP from organic sources. That technology may provide producers a way of objectively characterizing a farrowing room's suitability for a new group of sows to be moved into the farrowing room. Three ATP luminometers (Charm Sciences novaLUM II-X, 3M Clean Trace, and Neogen AccuPoint) were used to estimate relationships between ATP bioluminescence relative light units (RLU) and coliform plate counts (CPC). Five farrowing crate locations and the room entryway floor were swabbed to determine locations within a farrowing crate that can accurately estimate room cleanliness. Coliform plate counts were strongly correlated with Charm novaLUM II-X RLU (r = 0.70, P < 0.01). The Clean-Trace CPCs and RLU (r = 0.48, P < 0.01) were moderately correlated. There was a weak correlation between CPCs and AccuPoint RLU (r = 0.32, P < 0.01). The greatest area of surface contamination was the entryway floor and the sow feeder. Because CPCs and luminometer RLU were correlated, statistical process control charts were developed to provide cleanliness thresholds based on RLU values. Based on an adjusted 3σ from the mean RLU critical limit, 7.7% of crates for the Charm novaLUM II-X, 10.6% of crates for the 3M Clean Trace, and 0% of crates for the Neogen AccuPoint would have failed the critical limit for the sow feeder cleanliness thresholds. Using a similar approach, 11.4% of crates for the Charm novaLUM II-X, 10.5% of crates for the 3M Clean Trace, and 15.2% of crates for the Neogen AccuPoint would have failed the critical limit for the crate sorting bar cleanliness thresholds. These data suggest that ATP bioluminescence may be a reliable method to monitor cleaning effectiveness in farrowing rooms on commercial sow farms. Bioluminescence is a monitoring tool that should be used in conjunction with periodic microbial validation to monitor procedures for cleaning and disinfection.

Escherichia coli Orf135 (NudG) mutant protein specific for oxidized dATP.

Damaged 2'-deoxyribonucleotides cause mutations, cancer, cell death, and aging. The Escherichia coli Orf135 (NudG) protein catalyzes the hydrolysis of various 2'-deoxyribonucleotides including an oxidized form of dATP, 2-oxo-1,2-dihydro-2'-deoxyadenosine 5'-triphosphate (dAOTP, 2-hydroxy-2'-deoxyadenosine 5'-triphosphate). The best substrate is 5-methyl-2'-deoxycytidine 5'-triphosphate (dCmTP), and the protein prefers dCmTP over dAOTP by ∼200-fold in vitro. To make the enzyme specific for the mutagenic nucleotide dAOTP, a double mutant protein (E33A plus D118E) was designed and produced in E. coli. The purified mutant protein showed one order of magnitude higher dAOTP preference over dCmTP. The split protein based on this mutant may potentially be used to detect dAOTP in living cells.

Understanding metabolic plasticity at single cell resolution.

It is increasingly clear that cellular metabolic function varies not just between cells of different tissues, but also within tissues and cell types. In this essay, we envision how differences in central carbon metabolism arise from multiple sources, including the cell cycle, circadian rhythms, intrinsic metabolic cycles, and others. We also discuss and compare methods that enable such variation to be detected, including single-cell metabolomics and RNA-sequencing. We pay particular attention to biosensors for AMPK and central carbon metabolites, which when used in combination with metabolic perturbations, provide clear evidence of cellular variance in metabolic function.

Role of Exogenous Pyruvate in Maintaining Adenosine Triphosphate Production under High-Glucose Conditions through PARP-Dependent Glycolysis and PARP-Independent Tricarboxylic Acid Cycle.

Pyruvate serves as a key metabolite in energy production and as an anti-oxidant. In our previous study, exogenous pyruvate starvation under high-glucose conditions induced IMS32 Schwann cell death because of the reduced glycolysis-tricarboxylic acid (TCA) cycle flux and adenosine triphosphate (ATP) production. Thus, this study focused on poly-(ADP-ribose) polymerase (PARP) to investigate the detailed molecular mechanism of cell death. Rucaparib, a PARP inhibitor, protected Schwann cells against cell death and decreased glycolysis but not against an impaired TCA cycle under high-glucose conditions in the absence of pyruvate. Under such conditions, reduced pyruvate dehydrogenase (PDH) activity and glycolytic and mitochondrial ATP production were observed but not oxidative phosphorylation or the electric transfer chain. In addition, rucaparib supplementation restored glycolytic ATP production but not PDH activity and mitochondrial ATP production. No differences in the increased activity of caspase 3/7 and the localization of apoptosis-inducing factor were found among the experimental conditions. These results indicate that Schwann cells undergo necrosis rather than apoptosis or parthanatos under the aforementioned conditions. Exogenous pyruvate plays a pivotal role in maintaining the flux in PARP-dependent glycolysis and the PARP-independent TCA cycle in Schwann cells under high-glucose conditions.

Adenosine triphosphate release inhibitors targeting pannexin1 improve recovery after spinal cord injury.

Traumatic spinal cord injury is characterized by immediate and irreversible tissue loss at the lesion site and secondary tissue damage. Secondary injuries should, in principle, be preventable, although no effective treatment options currently exist for patients with acute spinal cord injury. Traumatized tissues release excessive amounts of adenosine triphosphate and activate the P2X purinoceptor 7/pannexin1 complex, which is associated with secondary injury. We investigated the neuroprotective effects of the blue dye Brilliant Blue FCF, a selective inhibitor of P2X purinoceptor 7/pannexin1 that is approved for use as a food coloring, by comparing it with Brilliant Blue G, a P2X7 purinoceptor antagonist, and carbenoxolone, which attenuates P2X purinoceptor 7/pannexin1 function, in a rat spinal cord injury model. Brilliant Blue FCF administered early after spinal cord injury reduced spinal cord anatomical damage and improved motor recovery without apparent toxicity. Brilliant Blue G had the highest effect on this neurological recovery, with Brilliant Blue FCF and carbenoxolone having comparable improvement. Furthermore, Brilliant Blue FCF administration reduced local astrocytic and microglial activation and neutrophil infiltration, and no differences in these histological effects were observed between compounds. Thus, Brilliant Blue FCF protects spinal cord neurons after spinal cord injury and suppresses local inflammatory responses as well as Brilliant Blue G and carbenoxolone.

Comparative study of myocardial perfusion and coronary flow velocity reserve derived from adenosine triphosphate stress myocardial contrast echocardiography in coronary lesions with no/mild stenosis.

Background: Qualitative myocardial perfusion (QMP) derived from myocardial contrast echocardiography reflects the capillary flow, while coronary flow velocity reserve from Doppler spectrum (D-CFVR) of the left anterior descending coronary artery (LAD) is used to assess coronary microvascular function, particularly after excluding severe epicardial coronary stenosis. The present study aimed to assess the relationship of QMP and D-CFVR in detecting coronary microvascular disease (CMVD) by using adenosine triphosphate stress myocardial contrast echocardiography (ATP stress MCE). Methods and results: Seventy-two patients (mean age: 54.22 ± 12.78 years) with chest pain and <50% coronary stenosis diagnosed by quantitative coronary angiography or dual-source CT underwent ATP stress MCE. The distribution of myocardial perfusion and CFVR value was estimated by experienced physicians. Of the 72 LAD with 0%-50% diameter stenosis, 15 (21%) exhibited abnormal CFVR and 31 (43%) displayed abnormal perfusion with ATP stress MCE. Eleven of the 15 LAD territories (73%) with abnormal CFVR values showed abnormal perfusion. However, CFVR was considered normal in 20 LAD territories (35%), despite the presence of perfusion defect in the territory. Conclusion: Abnormal myocardial perfusion during ATP stress MCE was found in a sizable percentage of patients in whom CFVR of the supplying vessel was considered normal.

Tryptophan Metabolism in Obesity: The Indoleamine 2,3-Dioxygenase-1 Activity and Therapeutic Options.

Obesity activates both innate and adaptive immune responses in adipose tissue. Adipose tissue macrophages are functional antigen-presenting cells that promote the proliferation of interferon-gamma (IFN-γ)-producing cluster of differentiation (CD)4+ T cells in adipose tissue of obese subjects. The increased formation of neopterin and degradation of tryptophan may result in decreased T-cell responsiveness and lead to immunodeficiency. The activity of inducible indoleamine 2,3-dioxygenase-1 (IDO1) plays a major role in pro-inflammatory, IFN-γ-dominated settings. The expression of several kynurenine pathway enzyme genes is significantly increased in obesity. IDO1 in obesity shifts tryptophan metabolism from serotonin and melatonin synthesis to the formation of kynurenines and increases the ratio of kynurenine to tryptophan as well as with neopterin production. Reduction in serotonin (5-hydroxytryptamine; 5-HT) production provokes satiety dysregulation that leads to increased caloric uptake and obesity. According to the monoamine-deficiency hypothesis, a deficiency of cerebral serotonin is involved in neuropsychiatric symptomatology of depression, mania, and psychosis. Indeed, bipolar disorder (BD) and related cognitive deficits are accompanied by a higher prevalence of overweight and obesity. Furthermore, the accumulation of amyloid-ß in Alzheimer's disease brains has several toxic effects as well as IDO induction. Hence, abdominal obesity is associated with vascular endothelial dysfunction. kynurenines and their ratios are prognostic parameters in coronary artery disease. Increased kynurenine/tryptophan ratio correlates with increased intima-media thickness and represents advanced atherosclerosis. However, after bariatric surgery, weight reduction does not lead to the normalization of IDO1 activity and atherosclerosis. IDO1 is involved in the mechanisms of immune tolerance and in the concept of tumor immuno-editing process in cancer development. Serum IDO1 activity is still used as a parameter in cancer development and growth. IDO-producing tumors show a high total IDO immunostaining score, and thus, using IDO inhibitors, such as Epacadostat, Navoximod, and L isomer of 1-methyl-tryptophan, seems an important modality for cancer treatment. There is an inverse correlation between serum folate concentration and body mass index, thus folate deficiency leads to hyperhomocysteinemia-induced oxidative stress. Immune checkpoint blockade targeting cytotoxic T-lymphocyte-associated protein-4 synergizes with imatinib, which is an inhibitor of mitochondrial folate-mediated one-carbon (1C) metabolism. Antitumor effects of imatinib are enhanced by increasing T-cell effector function in the presence of IDO inhibition. Combining IDO targeting with chemotherapy, radiotherapy and/or immunotherapy, may be an effective tool against a wide range of malignancies. However, there are some controversial results regarding the efficacy of IDO1 inhibitors in cancer treatment.

Biphasic effects of single-dose intravenous injection of uridine adenosine tetraphosphate on blood pressure in mice.

PURPOSE: To explore the effects of a single dose of uridine adenosine tetraphosphate (Up4A) administered through the tail vein, on the blood pressure of mice. METHODS: The mice were separated into three groups: the Up4A group, the norepinephrine (NA) group, and the α, ß-methylene adenosine triphosphate (α, ß-meATP) group. Each group of mice were injected drugs through the tail vein at 1, 3, 10, and 30 nmol/kg doses in an ascending order. Additionally, six mice were injected Up4A through the tail vein at 20, 40, 60, and 80 nmol/kg doses in an ascending order. The administration intervals for each dose were 20 min. RESULTS: Mice in these groups experienced a rapid increase in blood pressure, reaching its peak within 10 s after drug administration. It took approximately 120 s for the blood pressure to return to baseline levels after the administration of the drugs in both the NA and α, ß-meATP groups. After higher doses of Up4A were administered to the mice, their blood pressure exhibited biphasic changes. Initially, blood pressure of the mice rapidly dropped to a minimum within 10 s, then rose rapidly to a peak within 30 s. Subsequently, it gradually declined, taking around 10 min to return to the levels before the drug administration. CONCLUSION: Compared to NA and α, ß-meATP, Up4A, which contains purine and pyrimidine components, displayed a weaker blood pressure-elevating potency. Through its corresponding structure, Up4A exerted vasodilatory and vasoconstrictive effects throughout the entire experiment resulting in biphasic changes in blood pressure.

Allopurinol, Febuxostat, and Nonuse of Xanthine Oxidoreductase Inhibitor Treatment in Patients Receiving Hemodialysis: A Longitudinal Analysis.

Rationale & Objective: Allopurinol and febuxostat, which are xanthine oxidoreductase inhibitors, have been widely used as uric acid-lowering medications. However, evidence regarding their cardiovascular effects in hemodialysis is insufficient. This study compared the effects of allopurinol and febuxostat on mortality and cardiovascular outcomes in patients receiving hemodialysis. Study Design: A retrospective observational cohort study. Setting & Participants: Data of 6,791 patients who had no history of topiroxostat usage and underwent maintenance hemodialysis between March 2016 and March 2019 at Yokohama Daiichi Hospital, Zenjinkai, and its affiliated dialysis clinics in Japan's Kanagawa and Tokyo metropolitan areas were collected. Exposure: Allopurinol, febuxostat, and nontreatment. Outcomes: All-cause mortality, cardiovascular disease (CVD) events, heart failure (HF), acute myocardial infarction (AMI), and stroke. Analytical Approach: For the main analyses, marginal structural Cox proportional hazards models were used to estimate HRs adjusted for time-varying confounding and selection bias because of censoring. Results: Allopurinol and febuxostat showed significantly better survival than nontreatment for all-cause mortality (HR, 0.40; 95% CI, 0.30-0.54 and HR, 0.49; 95% CI, 0.38-0.63, respectively), without significant difference between allopurinol and febuxostat. Allopurinol showed significantly better survival than nontreatment, whereas febuxostat did not for CVD events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 1.01; 95% CI, 0.96-1.07, respectively), HF (HR, 0.71; 95% CI, 0.56-0.90 and HR, 1.03; 95% CI, 0.87-1.21, respectively), and AMI (HR, 0.48; 95% CI, 0.25-0.91 and HR, 0.76; 95% CI, 0.49-1.19, respectively). No comparisons showed significant results for stroke. Limitations: The ratio of renal or intestinal excretion of uric acid and uremic toxins could not be elucidated, and we could not investigate gene polymorphism because of the large number of cases. Conclusions: Allopurinol and febuxostat improved survival for all-cause mortality. Allopurinol and not febuxostat reduced the risk of CVD events, HF, and AMI.

Uric acid-lowering therapy has been used to prevent gout attacks and protect organs by reducing inflammation by lowering uric acid levels. However, uric acid-lowering medications have recently been found to have a side effect of inhibiting a channel responsible for excreting toxins, such as adenosine triphosphate-binding cassette transporter G2; the effects of medications with a strong inhibitory effect, such as febuxostat, are currently under investigation. Patients with kidney failure or dialysis excrete toxins through feces from their intestines in addition to removing toxins through dialysis. If uric acid-lowering medications suppress the channels responsible for intestinal toxin excretion, could this lead to the development of heart failure or stroke? This study investigated this question.