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Nature Chemical Biology Oct 2023Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity....
Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity. Here we show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase and directly activate the sGC-cGMP-PKG pathway without intermediacy of free NO. The NO-ferroheme species (with or without a protein carrier) efficiently relax isolated blood vessels and induce hypotension in rodents, which is greatly potentiated after the blockade of NOS activity. While free NO-induced relaxations are abolished by an NO scavenger and in the presence of red blood cells or blood plasma, a model compound, NO-ferroheme-myoglobin preserves its vasoactivity suggesting the physiological relevance of NO-ferroheme species. We conclude that NO-ferroheme behaves as a signaling entity in the vasculature.
Topics: Nitric Oxide; Erythrocytes; Heme; Signal Transduction
PubMed: 37710073
DOI: 10.1038/s41589-023-01411-5 -
Seminars in Respiratory and Critical... Oct 2023This article provides an overview of the journey of inspired oxygen after its uptake across the alveolar-capillary interface, and the interplay among tissue perfusion,...
This article provides an overview of the journey of inspired oxygen after its uptake across the alveolar-capillary interface, and the interplay among tissue perfusion, diffusion, and cellular respiration in the transport and utilization of oxygen. The critical interactions between oxygen and its facilitative carriers (hemoglobin in red blood cells and myoglobin in muscle cells), and with other respiratory and vasoactive molecules (carbon dioxide, nitric oxide, and carbon monoxide), are emphasized to illustrate how this versatile system dynamically optimizes regional convective transport and diffusive gas exchange. The rates of reciprocal gas exchange in the lung and the periphery must be well-matched and sufficient for meeting the range of energy demands from rest to maximal stress but not excessive as to become toxic. The mobile red blood cells play a vital role in matching tissue perfusion and gas exchange by dynamically regulating the controlled uptake of oxygen and communicating regional metabolic signals across different organs. Intracellular oxygen diffusion and facilitation via myoglobin into the mitochondria, and utilization via electron transport chain and oxidative phosphorylation, are summarized. Physiological and pathophysiological adaptations are briefly described. Dysfunction of any component across this integrated system affects all other components and elicits corresponding structural and functional adaptation aimed at matching the capacities across the entire system and restoring equilibrium under normal and pathological conditions.
Topics: Humans; Oxygen; Myoglobin; Lung; Cell Respiration; Perfusion; Oxygen Consumption
PubMed: 37541315
DOI: 10.1055/s-0043-1770061 -
Pflugers Archiv : European Journal of... May 2024Since more than a century, neuroscientists have distinguished excitatory (glutamatergic) neurons with long-distance projections from inhibitory (GABAergic) neurons with... (Review)
Review
Since more than a century, neuroscientists have distinguished excitatory (glutamatergic) neurons with long-distance projections from inhibitory (GABAergic) neurons with local projections and established layer-dependent schemes for the ~ 80% excitatory (principal) cells as well as the ~ 20% inhibitory neurons. Whereas, in the early days, mainly morphological criteria were used to define cell types, later supplemented by electrophysiological and neurochemical properties, nowadays. single-cell transcriptomics is the method of choice for cell type classification. Bringing recent insight together, we conclude that despite all established layer- and area-dependent differences, there is a set of reliably identifiable cortical cell types that were named (among others) intratelencephalic (IT), extratelencephalic (ET), and corticothalamic (CT) for the excitatory cells, which altogether comprise ~ 56 transcriptomic cell types (t-types). By the same means, inhibitory neurons were subdivided into parvalbumin (PV), somatostatin (SST), vasoactive intestinal polypeptide (VIP), and "other (i.e. Lamp5/Sncg)" subpopulations, which altogether comprise ~ 60 t-types. The coming years will show which t-types actually translate into "real" cell types that show a common set of multimodal features, including not only transcriptome but also physiology and morphology as well as connectivity and ultimately function. Only with the better knowledge of clear-cut cell types and experimental access to them, we will be able to reveal their specific functions, a task which turned out to be difficult in a part of the brain being so much specialized for cognition as the cerebral cortex.
Topics: Animals; Neurons; Humans; Cerebral Cortex; Transcriptome
PubMed: 38376567
DOI: 10.1007/s00424-024-02923-2 -
International Immunopharmacology Sep 2023Sepsis is is anabnormalhost immune responsecausedbyinfection. Antibiotics, anti-viral drugs, and vasoactive drugs have always been used in the traditional treatment of... (Review)
Review
Sepsis is is anabnormalhost immune responsecausedbyinfection. Antibiotics, anti-viral drugs, and vasoactive drugs have always been used in the traditional treatment of sepsis, but there are no specific and effective drugs in clinical practice. Autophagy is a highly conservative process in biological evolution, and plays an important role in maintaining intracellular homeostasis and cellular self-renewal. Autophagy can remove and degrade misfolding proteins and damaged organelles in cells, providing materials for cell repair and self-renewal. Hydrogen sulfide (HS) is a colorless gas that smells likerotteneggs. It is the third endogenous gas signal molecule discovered after nitric oxide and carbon monoxide and has become a research hotspot in recent years. HS has a variety of biological functions and plays an important role in various physiological and pathological processes. Thereisgrowingevidencethat HS can regulate autophagy. The intervention of autophagy is a promising therapeutic strategy to improve sepsis organ damage. This article reviews the organ protection of autophagy in sepsis and the role of HS in regulating autophagy in sepsis, revealing that HS intervention with autophagy may be a a worthy target in sepsis treatment.
Topics: Humans; Hydrogen Sulfide; Nitric Oxide; Carbon Monoxide; Autophagy; Sepsis
PubMed: 37473711
DOI: 10.1016/j.intimp.2023.110662 -
Current Opinion in Anaesthesiology Aug 2023This review describes recent prospective and retrospective work exploring the incidence and clinical consequence of sugammadex-induced bradycardia and an update of... (Review)
Review
PURPOSE OF REVIEW
This review describes recent prospective and retrospective work exploring the incidence and clinical consequence of sugammadex-induced bradycardia and an update of recent evidence and adverse event reports to the United States Food and Drug Administration regarding the incidence of sugammadex induced bradycardia.
RECENT FINDINGS
This work suggests that the incidence of sugammadex-induced bradycardia can range from 1 to 7% depending on the definition to reverse moderate to deep neuromuscular blockade. For most instances, the bradycardia is inconsequential. For those instances that have hemodynamic instability, the adverse physiology is easily treated with appropriate vasoactive agents. One study demonstrated that the incidence of bradycardia from sugammadex is less than with neostigmine. There are several case reports that describe marked bradycardia with cardiac arrest from reversal with sugammadex. The incidence of this type of reaction to sugammadex appears to be very rare. Data from the United States Food and Drug Administration's Adverse Event Reporting System public dashboard corroborates this presence of this rare finding.
SUMMARY
Sugammadex-induced bradycardia is common and, in most instances, of minimal clinical consequence. Nevertheless, anesthesia providers should maintain proper monitoring and vigilance to treat hemodynamical instability with each administration of sugammadex.
Topics: Humans; Sugammadex; Bradycardia; Retrospective Studies; Neostigmine; Neuromuscular Blockade
PubMed: 37314178
DOI: 10.1097/ACO.0000000000001282 -
Critical Care Medicine Dec 2023To identify cytokine signature clusters in patients with septic shock. (Observational Study)
Observational Study
OBJECTIVES
To identify cytokine signature clusters in patients with septic shock.
DESIGN
Prospective observational cohort study.
SETTING
Single academic center in the United States.
PATIENTS
Adult (≥ 18 yr old) patients admitted to the medical ICU with septic shock requiring vasoactive medication support.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
One hundred fourteen patients with septic shock completed cytokine measurement at time of enrollment (t 1 ) and 24 hours later (t 2 ). Unsupervised random forest analysis of the change in cytokines over time, defined as delta (t 2 -t 1 ), identified three clusters with distinct cytokine profiles. Patients in cluster 1 had the lowest initial levels of circulating cytokines that decreased over time. Patients in cluster 2 and cluster 3 had higher initial levels that decreased over time in cluster 2 and increased in cluster 3. Patients in clusters 2 and 3 had higher mortality compared with cluster 1 (clusters 1-3: 11% vs 31%; odds ratio [OR], 3.56 [1.10-14.23] vs 54% OR, 9.23 [2.89-37.22]). Cluster 3 was independently associated with in-hospital mortality (hazard ratio, 5.24; p = 0.005) in multivariable analysis. There were no significant differences in initial clinical severity scoring or steroid use between the clusters. Analysis of either t 1 or t 2 cytokine measurements alone or in combination did not reveal clusters with clear clinical significance.
CONCLUSIONS
Longitudinal measurement of cytokine profiles at initiation of vasoactive medications and 24 hours later revealed three distinct cytokine signature clusters that correlated with clinical outcomes.
Topics: Adult; Humans; United States; Shock, Septic; Prospective Studies; Cytokines
PubMed: 37678209
DOI: 10.1097/CCM.0000000000006032 -
Current Research in Physiology 2024Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such... (Review)
Review
Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such as diabetes mellitus, hypertension, and glomerulonephritis. Affecting over 10% of the global population, CKD stands as a significant cause of morbidity and mortality. Despite substantial advances in understanding CKD pathophysiology and management, there is still a need to explore novel mechanisms and potential therapeutic targets. Urotensin II (UII), a potent vasoactive peptide, has garnered attention for its possible role in the development and progression of CKD. The UII system consists of endogenous ligands UII and UII-related peptide (URP) and their receptor, UT. URP pathophysiology is understudied, but alterations in tissue expression levels of UII and UT and blood or urinary UII concentrations have been linked to cardiovascular and kidney dysfunctions, including systemic hypertension, chronic heart failure, glomerulonephritis, and diabetes. UII gene polymorphisms are associated with increased risk of diabetes. Pharmacological inhibition or genetic ablation of UT mitigated kidney and cardiovascular disease in rodents, making the UII system a potential target for slowing CKD progression. However, a deeper understanding of the UII system's cellular mechanisms in renal and extrarenal organs is essential for comprehending its role in CKD pathophysiology. This review explores the evolving connections between the UII system and CKD, addressing potential mechanisms, therapeutic implications, controversies, and unexplored concepts.
PubMed: 38779598
DOI: 10.1016/j.crphys.2024.100126 -
Cytoskeleton (Hoboken, N.J.) Jan 2024With 50 years to the original discovery of Tau, I gave here my perspective, looking through the prism of activity-dependent neuroprotective protein (ADNP), and the...
With 50 years to the original discovery of Tau, I gave here my perspective, looking through the prism of activity-dependent neuroprotective protein (ADNP), and the influence of sex. My starting point was vasoactive intestinal peptide (VIP), a regulator of ADNP. I then moved to the original discovery of ADNP and its active neuroprotective site, NAP, drug candidate, davunetide. Tau-ADNP-NAP interactions were then explained with emphasis on sex and future translational medicine.
PubMed: 37572043
DOI: 10.1002/cm.21776 -
Headache Sep 2023The purpose of this study was to investigate the serum levels of mitochondrial metabolism/reactive oxygen species (ROS)-related peptides (hypoxia inducible factor-1α...
OBJECTIVE
The purpose of this study was to investigate the serum levels of mitochondrial metabolism/reactive oxygen species (ROS)-related peptides (hypoxia inducible factor-1α [HIF-1α], fibroblast growth factor-21 [FGF-21], growth differentiation factor-15 [GDF-15]) and key migraine-related neuropeptides (calcitonin gene-related peptide [CGRP], pituitary adenylate cyclase-activating peptide-38 [PACAP-38], substance P [SP], and vasoactive intestinal peptide [VIP]) during migraine attacks and to evaluate their diagnostic value in pediatric migraine.
BACKGROUND
There is increasing evidence for the important role of impairment in oxidative mitochondrial metabolism in the pathophysiology of migraine. Potential biomarkers that may reflect the relationship between migraine and mitochondrial dysfunction are unclear.
METHODS
A total of 68 female pediatric migraine patients without aura and 20 female healthy controls aged 8-18 years, admitted to the hospital, were enrolled in this cross-sectional study. Serum concentrations of these molecules were determined by enzyme-linked immunosorbent assays, and clinical features and their possible diagnostic value were analyzed.
RESULTS
Serum levels of HIF-1α (252.4 ± 51.9 [mean ± standard deviation]) pg/mL), GDF-15 (233.7 ± 24.7 pg/mL), FGF-21 (96.1 ± 13.1 pg/mL), CGRP (44.5 ± 11.3), and PACAP-38 (504.7 ± 128.9) were significantly higher in migraine patients compared to healthy controls (199.8 ± 26.8, 192.8 ± 20.7, 79.3 ± 4.1, 34.1 ± 3.5 and 361.2 ± 86.3 pg/mL, respectively). The serum levels of these peptides were also higher in patients with chronic migraine than in patients with episodic migraine, and higher in the ictal period than in the interictal period. A positive correlation was found between attack frequency and both HIF-1α and FGF-21 levels in migraine patients. Serum levels of VIP and SP were not different between the migraine patients and healthy controls.
CONCLUSION
Migraine attacks are accompanied by elevated HIF-1α, FGF-21, GDF-15, CGRP, and PACAP-38 in medication-naive pediatric patients with migraine. Elevated circulating mitochondrial metabolism/ROS-related peptides suggest a mitochondrial stress in pediatric migraine attacks and may have potential diagnostic value in monitoring disease progression and treatment response in children. Novel approaches intervening with mitochondrial metabolism need to be investigated.
Topics: Humans; Child; Female; Growth Differentiation Factor 15; Calcitonin Gene-Related Peptide; Cross-Sectional Studies; Pituitary Adenylate Cyclase-Activating Polypeptide; Reactive Oxygen Species; Fibroblast Growth Factors; Mitochondria
PubMed: 37596867
DOI: 10.1111/head.14618 -
Journal of Biological Rhythms Apr 2024It has been 50 years since the suprachiasmatic nucleus (SCN) was first identified as the central circadian clock and 25 years since the last overview of developments... (Review)
Review
It has been 50 years since the suprachiasmatic nucleus (SCN) was first identified as the central circadian clock and 25 years since the last overview of developments in the field was published in the . Here, we explore new mechanisms and concepts that have emerged in the subsequent 25 years. Since 1997, methodological developments, such as luminescent and fluorescent reporter techniques, have revealed intricate relationships between cellular and network-level mechanisms. In particular, specific neuropeptides such as arginine vasopressin, vasoactive intestinal peptide, and gastrin-releasing peptide have been identified as key players in the synchronization of cellular circadian rhythms within the SCN. The discovery of multiple oscillators governing behavioral and physiological rhythms has significantly advanced our understanding of the circadian clock. The interaction between neurons and glial cells has been found to play a crucial role in regulating these circadian rhythms within the SCN. Furthermore, the properties of the SCN network vary across ontogenetic stages. The application of cell type-specific genetic manipulations has revealed components of the functional input-output system of the SCN and their correlation with physiological functions. This review concludes with the high-risk effort of identifying open questions and challenges that lie ahead.
Topics: Circadian Rhythm; Neuropeptides; Suprachiasmatic Nucleus; Vasoactive Intestinal Peptide; Gastrin-Releasing Peptide
PubMed: 38366616
DOI: 10.1177/07487304231225706